1-103003211-A-T

Variant names:

• chr1-103003211-A-T
• rs12136577
• NM_001854.4:c.1998+4T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001854.4(COL11A1):​c.1998+4T>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 0.13 in 1,612,950 control chromosomes in the GnomAD database, including 14,793 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 0.11 (1071 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13722 hom.)
• Consequence: COL11A1 NM_001854.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003112
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.211
• Publications: 7 publications found

Genes affected

COL11A1 (HGNC:2186): (collagen type XI alpha 1 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Mutations in this gene are associated with type II Stickler syndrome and with Marshall syndrome. A single-nucleotide polymorphism in this gene is also associated with susceptibility to lumbar disc herniation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

COL11A1 Gene-Disease associations (from GenCC):

• Marshall syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• Stickler syndrome type 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• fibrochondrogenesis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal dominant 37

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fibrochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-103003211-A-T is Benign according to our data. Variant chr1-103003211-A-T is described in ClinVar as Benign. ClinVar VariationId is 258440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001854.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	NM_001854.4	MANE Select	c.1998+4T>A		splice_region intron	N/A	NP_001845.3
	COL11A1	NM_080629.3		c.2034+4T>A		splice_region intron	N/A	NP_542196.2	P12107-2
	COL11A1	NM_001190709.2		c.1881+4T>A		splice_region intron	N/A	NP_001177638.1	P12107-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.1998+4T>A		splice_region intron	N/A	ENSP00000359114.3	P12107-1
	COL11A1	ENST00000512756.5	TSL:1	c.1650+4T>A		splice_region intron	N/A	ENSP00000426533.1	P12107-4
	COL11A1	ENST00000635193.1	TSL:1	n.1314+4T>A		splice_region intron	N/A	ENSP00000489428.1	A0A0U1RRA7

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16270 AN: 151944 Hom.: 1070 Cov.: 31

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.0919

GnomAD2 exomes AF: 0.123 AC: 30761 AN: 250108 AF XY: 0.121

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00142

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.132 AC: 192950 AN: 1460888 Hom.: 13722 Cov.: 34 AF XY: 0.131 AC XY: 95249 AN XY: 726696

African (AFR) AF: 0.0457 AC: 1531 AN: 33468

American (AMR) AF: 0.181 AC: 8092 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2969 AN: 26102

East Asian (EAS) AF: 0.00244 AC: 97 AN: 39690

South Asian (SAS) AF: 0.0738 AC: 6359 AN: 86180

European-Finnish (FIN) AF: 0.165 AC: 8806 AN: 53348

Middle Eastern (MID) AF: 0.135 AC: 780 AN: 5768

European-Non Finnish (NFE) AF: 0.141 AC: 156799 AN: 1111384

Other (OTH) AF: 0.125 AC: 7517 AN: 60338

GnomAD4 genome AF: 0.107 AC: 16276 AN: 152062 Hom.: 1071 Cov.: 31 AF XY: 0.107 AC XY: 7940 AN XY: 74350

African (AFR) AF: 0.0477 AC: 1980 AN: 41500

American (AMR) AF: 0.129 AC: 1968 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3464

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5176

South Asian (SAS) AF: 0.0645 AC: 311 AN: 4820

European-Finnish (FIN) AF: 0.161 AC: 1700 AN: 10570

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9615 AN: 67946

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

Alfa AF: 0.132 Hom.: 459

Bravo AF: 0.103

Asia WGS AF: 0.0400 AC: 137 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Fibrochondrogenesis 1 (2)
-	-	2	not provided (2)
-	-	2	Stickler syndrome type 2 (2)
-	-	1	Hearing loss, autosomal dominant 37 (1)
-	-	1	Marshall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.58
PhyloP100		-0.21
Mutation Taster		=39/61	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.042
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: rs12136577; hg19: chr1-103468767;