chr21-45987510-C-G

Position:

• chr21-45987510-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001848.3(COL6A1):​c.750C>G​(p.Phe250Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.54

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest N-terminal globular domain (size 236) in uniprot entity CO6A1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_001848.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19636995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.750C>G	p.Phe250Leu	missense_variant	7/35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.750C>G	p.Phe250Leu	missense_variant	7/35	1	NM_001848.3	ENSP00000355180.3
COL6A1	ENST00000492851.1	n.402C>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460706 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.750C>G (p.F250L) alteration is located in exon 7 (coding exon 7) of the COL6A1 gene. This alteration results from a C to G substitution at nucleotide position 750, causing the phenylalanine (F) at amino acid position 250 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	0.059	D
MutationAssessor	Benign	2.0	M;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.50
Sift	Benign	0.45	T;.
Sift4G	Benign	0.25	T;T
Polyphen		0.92	P;.
Vest4		0.30
MutPred		0.33		Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);
MVP		0.65
MPC		0.26
ClinPred		0.93	D
GERP RS		0.79
Varity_R		0.11
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs748153811; hg19: chr21-47407424;