rs41317345

Variant names:

• chr17-50199746-G-T
• rs41317345
• NM_000088.4:c.298+7C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000088.4(COL1A1):​c.298+7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,610,402 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (45 hom.)
• Consequence: COL1A1 NM_000088.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004996
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.19
• Publications: 2 publications found

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

TILAM (HGNC:52795): (long intergenic non-protein coding RNA 1969)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-50199746-G-T is Benign according to our data. Variant chr17-50199746-G-T is described in ClinVar as Benign. ClinVar VariationId is 324120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1893/151712) while in subpopulation AFR AF = 0.0427 (1765/41366). AF 95% confidence interval is 0.041. There are 27 homozygotes in GnomAd4. There are 918 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1893 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.298+7C>A		splice_region_variant, intron_variant	Intron 2 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.298+7C>A		splice_region_variant, intron_variant	Intron 2 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.298+7C>A		splice_region_variant, intron_variant	Intron 2 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.298+7C>A		splice_region_variant, intron_variant	Intron 2 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.298+7C>A		splice_region_variant, intron_variant	Intron 2 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000507689.1	c.352+7C>A		splice_region_variant, intron_variant	Intron 1 of 3	2		ENSP00000460459.1
COL1A1	ENST00000474644.1	n.417+7C>A		splice_region_variant, intron_variant	Intron 2 of 3	3
TILAM	ENST00000509943.2	n.-130G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1897 AN: 151600 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00871

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00960

GnomAD2 exomes AF: 0.00365 AC: 882 AN: 241942 AF XY: 0.00260

Gnomad AFR exome AF: 0.0444

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00578

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.00136 AC: 1981 AN: 1458690 Hom.: 45 Cov.: 35 AF XY: 0.00119 AC XY: 863 AN XY: 725608

African (AFR) AF: 0.0421 AC: 1407 AN: 33410

American (AMR) AF: 0.00181 AC: 81 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00597 AC: 237 AN: 39686

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52486

Middle Eastern (MID) AF: 0.00131 AC: 6 AN: 4576

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111392

Other (OTH) AF: 0.00286 AC: 172 AN: 60204

GnomAD4 genome AF: 0.0125 AC: 1893 AN: 151712 Hom.: 27 Cov.: 32 AF XY: 0.0124 AC XY: 918 AN XY: 74108

African (AFR) AF: 0.0427 AC: 1765 AN: 41366

American (AMR) AF: 0.00366 AC: 56 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00835 AC: 43 AN: 5150

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67868

Other (OTH) AF: 0.00950 AC: 20 AN: 2106

Alfa AF: 0.00435 Hom.: 3

Bravo AF: 0.0143

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 06, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 08, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ehlers-Danlos syndrome Benign:1

Jan 31, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Infantile cortical hyperostosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Osteogenesis imperfecta type I Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.1
DANN	Benign	0.44
PhyloP100		-1.2
PromoterAI		-0.11	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41317345; hg19: chr17-48277107;