rs149832668

Positions:

• chr6-75175268-G-A
• chr6-75175268-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_004370.6(COL12A1):​c.2480C>T​(p.Thr827Met) variant causes a missense change. The variant allele was found at a frequency of 0.000377 in 1,614,084 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T827T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (6 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.66

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.01568389).
• BP6: Variant 6-75175268-G-A is Benign according to our data. Variant chr6-75175268-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 542513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000191 (29/152208) while in subpopulation EAS AF= 0.00521 (27/5178). AF 95% confidence interval is 0.00368. There are 1 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.2480C>T	p.Thr827Met	missense_variant	13/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.2480C>T	p.Thr827Met	missense_variant	13/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.74-22786C>T		intron_variant		1
COL12A1	ENST00000483888.6	c.2480C>T	p.Thr827Met	missense_variant	13/65	5		A1
COL12A1	ENST00000416123.6	c.2480C>T	p.Thr827Met	missense_variant	12/63	5

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152090 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000197 AC: 49 AN: 249304 Hom.: 1 AF XY: 0.000163 AC XY: 22 AN XY: 135242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00206

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000396 AC: 579 AN: 1461876 Hom.: 6 Cov.: 31 AF XY: 0.000388 AC XY: 282 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0135

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000240 AC: 29

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.70	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.23	T;T;T
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.69	P;.;.
Vest4		0.54
MVP		0.48
MPC		0.58
ClinPred		0.067	T
GERP RS		5.8
Varity_R		0.055
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs149832668; hg19: chr6-75884984; COSMIC: COSV59390229; COSMIC: COSV59390229;