6-56057820-C-T

Variant names:

• chr6-56057820-C-T
• rs766194518
• NM_030820.4:c.2711G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030820.4(COL21A1):​c.2711G>A​(p.Ser904Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000063 in 1,428,852 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: 0.0000063 (0 hom.)
• Consequence: COL21A1 NM_030820.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

Genes affected

COL21A1 (HGNC:17025): (collagen type XXI alpha 1 chain) This gene encodes the alpha chain of type XXI collagen, a member of the FACIT (fibril-associated collagens with interrupted helices) collagen family. Type XXI collagen is localized to tissues containing type I collagen and maintains the integrity of the extracellular matrix. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33930707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL21A1	NM_030820.4	c.2711G>A	p.Ser904Asn	missense_variant	Exon 30 of 30	ENST00000244728.10	NP_110447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL21A1	ENST00000244728.10	c.2711G>A	p.Ser904Asn	missense_variant	Exon 30 of 30	1	NM_030820.4	ENSP00000244728.5
COL21A1	ENST00000370819.5	c.2702G>A	p.Ser901Asn	missense_variant	Exon 29 of 29	1		ENSP00000359855.1
COL21A1	ENST00000488912.5	n.*857G>A		non_coding_transcript_exon_variant	Exon 18 of 18	1		ENSP00000433624.1
COL21A1	ENST00000488912.5	n.*857G>A		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000433624.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000630 AC: 9 AN: 1428852 Hom.: 0 Cov.: 31 AF XY: 0.00000705 AC XY: 5 AN XY: 709418

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000729

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000372 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2711G>A (p.S904N) alteration is located in exon 30 (coding exon 29) of the COL21A1 gene. This alteration results from a G to A substitution at nucleotide position 2711, causing the serine (S) at amino acid position 904 to be replaced by an asparagine (N). 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	Benign	0.25
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.035	T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.58	N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.17	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.31
MVP		0.73
MPC		0.019
ClinPred		0.52	D
GERP RS		4.2
Varity_R		0.18
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766194518; hg19: chr6-55922618;