chr8-138594081-C-A

Variant names:

• chr8-138594081-C-A
• rs531509761
• NM_152888.3:c.4551G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152888.3(COL22A1):​c.4551G>T​(p.Met1517Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,590,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: COL22A1 NM_152888.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.15
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056306034).

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.4551G>T	p.Met1517Ile	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.4551G>T	p.Met1517Ile	missense	Exon 63 of 65	ENSP00000303153.6	Q8NFW1-1
	COL22A1	ENST00000341807.8	TSL:1	n.2236G>T		non_coding_transcript_exon	Exon 37 of 39
	COL22A1	ENST00000903590.1		c.4491G>T	p.Met1497Ile	missense	Exon 62 of 64	ENSP00000573649.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 27 AN: 224164 AF XY: 0.000146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000712

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000241

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000261 AC: 376 AN: 1438112 Hom.: 0 Cov.: 31 AF XY: 0.000249 AC XY: 178 AN XY: 716064

African (AFR) AF: 0.0000646 AC: 2 AN: 30936

American (AMR) AF: 0.000209 AC: 8 AN: 38228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 37884

South Asian (SAS) AF: 0.00 AC: 0 AN: 83676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.000312 AC: 345 AN: 1104084

Other (OTH) AF: 0.000354 AC: 21 AN: 59318

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74482

African (AFR) AF: 0.0000481 AC: 2 AN: 41584

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.18	N
PhyloP100		-1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.25
Sift	Benign	0.47	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.33		Gain of catalytic residue at M1517 (P = 0.0573)
MVP		0.51
MPC		0.093
ClinPred		0.040	T
GERP RS		3.1
Varity_R		0.091
gMVP		0.11
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs531509761; hg19: chr8-139606324;