rs41292523

Variant names:

• chr1-102876928-T-A
• rs41292523
• NM_001854.4:c.*1091A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001854.4(COL11A1):​c.*1091A>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 0.00182 in 152,548 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (0 hom.)
• Consequence: COL11A1 NM_001854.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0630
• Publications: 0 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Stickler syndrome type 2

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-102876928-T-A is Benign according to our data. Variant chr1-102876928-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 291479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00181 (276/152176) while in subpopulation NFE AF = 0.00281 (191/67954). AF 95% confidence interval is 0.00248. There are 1 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*1091A>T		3_prime_UTR	Exon 67 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.*1091A>T		3_prime_UTR	Exon 67 of 67	NP_542196.2	P12107-2
	COL11A1	NM_001190709.2		c.*1091A>T		3_prime_UTR	Exon 66 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.*1091A>T		3_prime_UTR	Exon 67 of 67	ENSP00000359114.3	P12107-1
	COL11A1	ENST00000358392.6	TSL:5	c.*1091A>T		3_prime_UTR	Exon 67 of 67	ENSP00000351163.2	P12107-2
	COL11A1	ENST00000353414.8	TSL:5	c.*1091A>T		3_prime_UTR	Exon 66 of 66	ENSP00000302551.6	P12107-3

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 276 AN: 152058 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00269 AC: 1 AN: 372 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 226

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00273 AC: 1 AN: 366

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152176 Hom.: 1 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74406

African (AFR) AF: 0.000457 AC: 19 AN: 41564

American (AMR) AF: 0.00118 AC: 18 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 67954

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00148

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Fibrochondrogenesis 1 (1)
-	-	1	Stickler syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.0
DANN	Benign	0.66
PhyloP100		-0.063

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: rs41292523; hg19: chr1-103342484;