rs141548164

Variant names:

• chr1-102979414-A-T
• rs141548164
• NM_001854.4:c.2578T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-102979414-A-T
• chr1-102979414-A-C

Variant summary

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

The NM_001854.4(COL11A1):​c.2578T>A​(p.Phe860Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,609,822 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (43 hom.)
• Consequence: COL11A1 NM_001854.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 8.85
• Publications: 15 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 (MetaRNN=0.010059297).
• BP6: Variant 1-102979414-A-T is Benign according to our data. Variant chr1-102979414-A-T is described in ClinVar as Benign. ClinVar VariationId is 196779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.005 (761/152336) while in subpopulation AMR AF = 0.0218 (334/15304). AF 95% confidence interval is 0.0199. There are 6 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.2578T>A	p.Phe860Ile	missense	Exon 32 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.2614T>A	p.Phe872Ile	missense	Exon 32 of 67	NP_542196.2	P12107-2
	COL11A1	NM_001190709.2		c.2461T>A	p.Phe821Ile	missense	Exon 31 of 66	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.2578T>A	p.Phe860Ile	missense	Exon 32 of 67	ENSP00000359114.3	P12107-1
	COL11A1	ENST00000512756.5	TSL:1	c.2230T>A	p.Phe744Ile	missense	Exon 30 of 65	ENSP00000426533.1	P12107-4
	COL11A1	ENST00000635193.1	TSL:1	n.1910T>A		non_coding_transcript_exon	Exon 29 of 64	ENSP00000489428.1	A0A0U1RRA7

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 760 AN: 152218 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00769 AC: 1926 AN: 250608 AF XY: 0.00632

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00397

Gnomad OTH exome AF: 0.00639

GnomAD4 exome AF: 0.00482 AC: 7030 AN: 1457486 Hom.: 43 Cov.: 29 AF XY: 0.00461 AC XY: 3341 AN XY: 725352

African (AFR) AF: 0.000749 AC: 25 AN: 33386

American (AMR) AF: 0.0284 AC: 1270 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26098

East Asian (EAS) AF: 0.0132 AC: 522 AN: 39670

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86142

European-Finnish (FIN) AF: 0.00390 AC: 208 AN: 53378

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00427 AC: 4731 AN: 1108144

Other (OTH) AF: 0.00407 AC: 245 AN: 60238

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152336 Hom.: 6 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74502

African (AFR) AF: 0.00115 AC: 48 AN: 41574

American (AMR) AF: 0.0218 AC: 334 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0104 AC: 54 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00428 AC: 291 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00396 Hom.: 0

Bravo AF: 0.00599

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00646 AC: 784

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	7	not specified (7)
-	-	1	Connective tissue disorder (1)
-	-	1	Fibrochondrogenesis 1 (1)
-	-	1	Stickler syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.015	N
PhyloP100		8.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.65
Sift	Benign	0.22	T
Sift4G	Benign	0.30	T
Polyphen		0.98	D
Vest4		0.56
MVP		0.64
MPC		0.17
ClinPred		0.039	T
GERP RS		5.0
Varity_R		0.35
gMVP		0.78
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs141548164; hg19: chr1-103444970; COSMIC: COSV109431013;