8-138594081-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 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. 16/21 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

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056306034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL22A1	NM_152888.3	c.4551G>T	p.Met1517Ile	missense_variant	63/65	ENST00000303045.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL22A1	ENST00000303045.11	c.4551G>T	p.Met1517Ile	missense_variant	63/65	1	NM_152888.3	P1
COL22A1	ENST00000341807.8	n.2236G>T		non_coding_transcript_exon_variant	37/39	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

GnomAD3 exomes AF: 0.000120 AC: 27 AN: 224164 Hom.: 0 AF XY: 0.000146 AC XY: 18 AN XY: 122970

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 SAS 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

Gnomad4 AFR exome AF: 0.0000646

Gnomad4 AMR exome AF: 0.000209

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: 0.000312

Gnomad4 OTH exome AF: 0.000354

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.4551G>T (p.M1517I) alteration is located in exon 63 (coding exon 62) of the COL22A1 gene. This alteration results from a G to T substitution at nucleotide position 4551, causing the methionine (M) at amino acid position 1517 to be replaced by an isoleucine (I). 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	0.14
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;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.18	N;.
MutationTaster	Benign	0.90	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.25
Sift	Benign	0.47	T;.
Sift4G	Benign	0.24	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs531509761; hg19: chr8-139606324;