8-138594191-C-T

Variant names:

• chr8-138594191-C-T
• rs748343987
• NM_152888.3:c.4441G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152888.3(COL22A1):​c.4441G>A​(p.Ala1481Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,569,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1481S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: COL22A1 NM_152888.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.09
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37565547).

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.4441G>A	p.Ala1481Thr	missense	Exon 63 of 65	NP_690848.1	Q8NFW1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL22A1	ENST00000303045.11	TSL:1 MANE Select	c.4441G>A	p.Ala1481Thr	missense	Exon 63 of 65	ENSP00000303153.6	Q8NFW1-1
	COL22A1	ENST00000341807.8	TSL:1	n.2126G>A		non_coding_transcript_exon	Exon 37 of 39
	COL22A1	ENST00000903590.1		c.4381G>A	p.Ala1461Thr	missense	Exon 62 of 64	ENSP00000573649.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 5 AN: 205768 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.0000411

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000275 AC: 39 AN: 1417572 Hom.: 0 Cov.: 31 AF XY: 0.0000199 AC XY: 14 AN XY: 705180

African (AFR) AF: 0.00 AC: 0 AN: 29470

American (AMR) AF: 0.00 AC: 0 AN: 34294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24550

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35894

South Asian (SAS) AF: 0.0000374 AC: 3 AN: 80306

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.0000292 AC: 32 AN: 1095844

Other (OTH) AF: 0.0000171 AC: 1 AN: 58556

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74432

African (AFR) AF: 0.0000481 AC: 2 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0017	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.25		Gain of phosphorylation at A1481 (P = 0.06)
MVP		0.55
MPC		0.081
ClinPred		0.29	T
GERP RS		5.9
Varity_R		0.083
gMVP		0.12
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs748343987; hg19: chr8-139606434; COSMIC: COSV57324048;