rs4909444

Variant names:

• chr8-138688966-G-T
• rs4909444
• NM_152888.3:c.2813C>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 30 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152888.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL22A1	NM_152888.3	MANE Select	c.2813C>A	p.Ala938Asp	missense	Exon 37 of 65	NP_690848.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL22A1	ENST00000303045.11	TSL:1 MANE Select	c.2813C>A	p.Ala938Asp	missense	Exon 37 of 65	ENSP00000303153.6
	COL22A1	ENST00000341807.8	TSL:1	n.558C>A		non_coding_transcript_exon	Exon 12 of 39
	COL22A1	ENST00000903590.1		c.2813C>A	p.Ala938Asp	missense	Exon 37 of 64	ENSP00000573649.1

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

GnomAD2 exomes AF: 0.330 AC: 82824 AN: 251314 AF XY: 0.333

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 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

African (AFR) AF: 0.272 AC: 9052 AN: 33338

American (AMR) AF: 0.336 AC: 15039 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 6277 AN: 26110

East Asian (EAS) AF: 0.239 AC: 9488 AN: 39682

South Asian (SAS) AF: 0.387 AC: 33353 AN: 86096

European-Finnish (FIN) AF: 0.428 AC: 22845 AN: 53394

Middle Eastern (MID) AF: 0.269 AC: 1550 AN: 5760

European-Non Finnish (NFE) AF: 0.327 AC: 361950 AN: 1105240

Other (OTH) AF: 0.317 AC: 19066 AN: 60158

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

African (AFR) AF: 0.270 AC: 11193 AN: 41390

American (AMR) AF: 0.309 AC: 4711 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3470

East Asian (EAS) AF: 0.202 AC: 1039 AN: 5142

South Asian (SAS) AF: 0.397 AC: 1906 AN: 4796

European-Finnish (FIN) AF: 0.428 AC: 4509 AN: 10538

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.331 AC: 22512 AN: 67916

Other (OTH) AF: 0.309 AC: 652 AN: 2110

Alfa AF: 0.319 Hom.: 29804

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 v4.9

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
MetaRNN	Benign	0.00032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N
PhyloP100		1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.16
Sift	Benign	0.63	T
Sift4G	Benign	0.21	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
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4909444; hg19: chr8-139701209; COSMIC: COSV57334932;