rs72727814

Variant names:

• chr8-138594184-A-T
• rs72727814
• NM_152888.3:c.4448T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_152888.3(COL22A1):​c.4448T>A​(p.Leu1483His) variant causes a missense change. The variant allele was found at a frequency of 0.00616 in 1,572,466 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (52 hom.)
• Consequence: COL22A1 NM_152888.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.07
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008943975).
• BP6: Variant 8-138594184-A-T is Benign according to our data. Variant chr8-138594184-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2658850.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 gene

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.4448T>A	p.Leu1483His	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.4448T>A	p.Leu1483His	missense	Exon 63 of 65	ENSP00000303153.6	Q8NFW1-1
	COL22A1	ENST00000341807.8	TSL:1	n.2133T>A		non_coding_transcript_exon	Exon 37 of 39
	COL22A1	ENST00000903590.1		c.4388T>A	p.Leu1463His	missense	Exon 62 of 64	ENSP00000573649.1

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 911 AN: 152198 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00630

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00669 AC: 1395 AN: 208650 AF XY: 0.00653

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0453

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00809

GnomAD4 exome AF: 0.00617 AC: 8769 AN: 1420150 Hom.: 52 Cov.: 31 AF XY: 0.00618 AC XY: 4365 AN XY: 706504

African (AFR) AF: 0.000910 AC: 27 AN: 29660

American (AMR) AF: 0.00195 AC: 68 AN: 34816

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 1080 AN: 24668

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36152

South Asian (SAS) AF: 0.000707 AC: 57 AN: 80592

European-Finnish (FIN) AF: 0.0164 AC: 869 AN: 53050

Middle Eastern (MID) AF: 0.00195 AC: 11 AN: 5644

European-Non Finnish (NFE) AF: 0.00567 AC: 6224 AN: 1096920

Other (OTH) AF: 0.00737 AC: 432 AN: 58648

GnomAD4 genome AF: 0.00598 AC: 911 AN: 152316 Hom.: 6 Cov.: 33 AF XY: 0.00639 AC XY: 476 AN XY: 74478

African (AFR) AF: 0.00108 AC: 45 AN: 41576

American (AMR) AF: 0.00555 AC: 85 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00631 AC: 429 AN: 68034

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00946 Hom.: 4

Bravo AF: 0.00516

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00575 AC: 698

Asia WGS AF: 0.00144 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.0070	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.45
MVP		0.50
MPC		0.11
ClinPred		0.030	T
GERP RS		5.9
Varity_R		0.26
gMVP		0.47
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72727814; hg19: chr8-139606427; COSMIC: COSV99079059;