rs77654847

Variant names:

• chr6-75142113-A-C
• rs77654847
• NM_004370.6:c.4876T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.4876T>G​(p.Ser1626Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000685 in 1,614,140 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (5 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.22

Genes affected

COL12A1 (HGNC:2188): (collagen type XII alpha 1 chain) This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008573294).
• BP6: Variant 6-75142113-A-C is Benign according to our data. Variant chr6-75142113-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 542499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75142113-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00385 (586/152304) while in subpopulation AFR AF= 0.0137 (568/41568). AF 95% confidence interval is 0.0127. There are 8 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.4876T>G	p.Ser1626Ala	missense_variant	Exon 27 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.4876T>G	p.Ser1626Ala	missense_variant	Exon 27 of 66	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152186 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000922 AC: 230 AN: 249406 Hom.: 4 AF XY: 0.000695 AC XY: 94 AN XY: 135288

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000356 AC: 520 AN: 1461836 Hom.: 5 Cov.: 30 AF XY: 0.000290 AC XY: 211 AN XY: 727222

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00385 AC: 586 AN: 152304 Hom.: 8 Cov.: 32 AF XY: 0.00377 AC XY: 281 AN XY: 74486

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000649 Hom.: 1

Bravo AF: 0.00420

ESP6500AA AF: 0.0112 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00120 AC: 145

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

May 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 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
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;T;T
MetaRNN	Benign	0.0086	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	.;M;.;M;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	.;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.25	.;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.99, 1.0	.;D;D;.;.
Vest4		0.42
MVP		0.62
MPC		0.52
ClinPred		0.041	T
GERP RS		6.2
Varity_R		0.11
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77654847; hg19: chr6-75851829;