rs4909444

Positions:

• chr8-138688966-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152888.3(COL22A1):​c.2813C>A​(p.Ala938Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,606,310 control chromosomes in the GnomAD database, including 88,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (7660 hom., cov: 30)
  • Exomes 𝑓: 0.33 (80936 hom.)
• Consequence: COL22A1 NM_152888.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39

Genes affected

COL22A1 (HGNC:22989): (collagen type XXII alpha 1 chain) This gene encodes member of the collagen family which is thought to contribute to the stabilization of myotendinous junctions and strengthen skeletal muscle attachments during contractile activity. It belongs to the fibril-associated collagens with interrupted triple helix (FACIT) subset of the collagen superfamily, which associate with collagen fibers through their C-terminal collagenous domains and mediate protein-protein interactions through their N-terminal noncollagenous domains. The encoded protein is deposited in the basement membrane zone of the myotendinous junction which is present only at the tissue junctions of muscles, tendons, the heart, articular cartilage, and skin. A knockdown of the orthologous zebrafish gene induces a muscular dystrophy by disruption of the myotendinous junction. [provided by RefSeq, May 2017]

COL22A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1664968E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL22A1	NM_152888.3	c.2813C>A	p.Ala938Asp	missense_variant	37/65	ENST00000303045.11	NP_690848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL22A1	ENST00000303045.11	c.2813C>A	p.Ala938Asp	missense_variant	37/65	1	NM_152888.3	ENSP00000303153.6
COL22A1	ENST00000341807.8	n.558C>A		non_coding_transcript_exon_variant	12/39	1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47697 AN: 151712 Hom.: 7657 Cov.: 30

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.330 AC: 82824 AN: 251314 Hom.: 14279 AF XY: 0.333 AC XY: 45194 AN XY: 135824

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.198

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.329 AC: 478620 AN: 1454478 Hom.: 80936 Cov.: 32 AF XY: 0.330 AC XY: 239021 AN XY: 723982

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.387

Gnomad4 FIN exome AF: 0.428

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.317

GnomAD4 genome AF: 0.314 AC: 47730 AN: 151832 Hom.: 7660 Cov.: 30 AF XY: 0.321 AC XY: 23781 AN XY: 74190

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.428

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.309

Alfa AF: 0.320 Hom.: 20249

Bravo AF: 0.302

TwinsUK AF: 0.335 AC: 1244

ALSPAC AF: 0.332 AC: 1278

ESP6500AA AF: 0.288 AC: 1269

ESP6500EA AF: 0.328 AC: 2821

ExAC AF: 0.329 AC: 39907

Asia WGS AF: 0.314 AC: 1095 AN: 3478

EpiCase AF: 0.325

EpiControl AF: 0.324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.76
DEOGEN2	Benign	0.0012	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.00032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.16
Sift	Benign	0.63	T;.
Sift4G	Benign	0.21	T;T
Polyphen		0.037	B;.
Vest4		0.18
MPC		0.13
ClinPred		0.0027	T
GERP RS		2.7
Varity_R		0.085
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs4909444; hg19: chr8-139701209; COSMIC: COSV57334932;