6-116119758-T-A

Variant names:

• chr6-116119758-T-A
• rs566937288
• NM_000493.4:c.*315A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000493.4(COL10A1):​c.*315A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 200,764 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (2 hom.)
• Consequence: COL10A1 NM_000493.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.23
• Publications: 0 publications found

Genes affected

COL10A1 (HGNC:2185): (collagen type X alpha 1 chain) This gene encodes the alpha chain of type X collagen, a short chain collagen expressed by hypertrophic chondrocytes during endochondral ossification. Unlike type VIII collagen, the other short chain collagen, type X collagen is a homotrimer. Mutations in this gene are associated with Schmid type metaphyseal chondrodysplasia (SMCD) and Japanese type spondylometaphyseal dysplasia (SMD). [provided by RefSeq, Jul 2008]

NT5DC1 (HGNC:21556): (5'-nucleotidase domain containing 1) While the exact function of the protein encoded by this gene is not known, it belongs to the 5'(3')-deoxyribonucleotidase family. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-116119758-T-A is Benign according to our data. Variant chr6-116119758-T-A is described in ClinVar as [Benign]. Clinvar id is 355083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00287 (396/137764) while in subpopulation SAS AF = 0.0479 (207/4320). AF 95% confidence interval is 0.0426. There are 9 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 396 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.*315A>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+1813T>A		intron_variant	Intron 6 of 11	ENST00000319550.9	NP_689942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1	c.*315A>T		3_prime_UTR_variant	Exon 3 of 3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+1813T>A		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 392 AN: 137666 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00192

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.00522

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00313

GnomAD4 exome AF: 0.00259 AC: 163 AN: 63000 Hom.: 2 Cov.: 0 AF XY: 0.00284 AC XY: 91 AN XY: 32090

African (AFR) AF: 0.00101 AC: 2 AN: 1986

American (AMR) AF: 0.000913 AC: 3 AN: 3286

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 32 AN: 2200

East Asian (EAS) AF: 0.00338 AC: 16 AN: 4734

South Asian (SAS) AF: 0.0261 AC: 77 AN: 2954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000470 AC: 19 AN: 40446

Other (OTH) AF: 0.00339 AC: 14 AN: 4126

GnomAD4 genome AF: 0.00287 AC: 396 AN: 137764 Hom.: 9 Cov.: 32 AF XY: 0.00366 AC XY: 247 AN XY: 67418

African (AFR) AF: 0.000130 AC: 5 AN: 38430

American (AMR) AF: 0.00192 AC: 27 AN: 14078

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 65 AN: 3180

East Asian (EAS) AF: 0.00523 AC: 26 AN: 4970

South Asian (SAS) AF: 0.0479 AC: 207 AN: 4320

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000911 AC: 55 AN: 60372

Other (OTH) AF: 0.00515 AC: 10 AN: 1940

Alfa AF: 0.000614 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0090
DANN	Benign	0.13
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs566937288; hg19: chr6-116440921; COSMIC: COSV99683999; COSMIC: COSV99683999;