10-133268049-C-T

Variant names:

• chr10-133268049-C-T
• rs761271202
• ENST00000415217.7:c.1966G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001164489.2(ADAM8):​c.1966G>A​(p.Gly656Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000411 in 1,265,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ADAM8 NM_001164489.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.94
• Publications: 0 publications found

Genes affected

ADAM8 (HGNC:215): (ADAM metallopeptidase domain 8) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The protein encoded by this gene may be involved in cell adhesion during neurodegeneration, and it is thought to be a target for allergic respiratory diseases, including asthma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083288044).
• BP6: Variant 10-133268049-C-T is Benign according to our data. Variant chr10-133268049-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3266208.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164489.2. 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
	ADAM8	NM_001109.5	MANE Select	c.2133G>A	p.Pro711Pro	synonymous	Exon 20 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164489.2		c.1966G>A	p.Gly656Ser	missense	Exon 19 of 22	NP_001157961.1	P78325-3
	ADAM8	NM_001164490.2		c.1938G>A	p.Pro646Pro	synonymous	Exon 18 of 20	NP_001157962.1	P78325-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM8	ENST00000415217.7	TSL:1	c.1966G>A	p.Gly656Ser	missense	Exon 19 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.2133G>A	p.Pro711Pro	synonymous	Exon 20 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000897047.1		c.2127G>A	p.Pro709Pro	synonymous	Exon 20 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000276 AC: 1 AN: 36234 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: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000440 AC: 49 AN: 1113194 Hom.: 0 Cov.: 32 AF XY: 0.0000379 AC XY: 20 AN XY: 527468

African (AFR) AF: 0.0000420 AC: 1 AN: 23824

American (AMR) AF: 0.00 AC: 0 AN: 11000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14558

East Asian (EAS) AF: 0.0000360 AC: 1 AN: 27750

South Asian (SAS) AF: 0.00 AC: 0 AN: 20998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.0000473 AC: 44 AN: 930320

Other (OTH) AF: 0.0000674 AC: 3 AN: 44512

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000951 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.4
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.00040	T
MetaRNN	Benign	0.083	T
PhyloP100		-2.9
PROVEAN	Benign	0.18	N
Sift	Benign	0.077	T
Sift4G	Benign	0.14	T
Vest4		0.11
MVP		0.50
GERP RS		-3.3
Mutation Taster		=99/1	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: rs761271202; hg19: chr10-135081553;