10-133267938-C-G

Variant names:

• chr10-133267938-C-G
• rs1483847365
• ENST00000415217.7:c.2077G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164489.2(ADAM8):​c.2077G>C​(p.Ala693Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict 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. A693T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAM8 NM_001164489.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.49
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080856144).

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.2244G>C	p.Pro748Pro	synonymous	Exon 20 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164489.2		c.2077G>C	p.Ala693Pro	missense	Exon 19 of 22	NP_001157961.1	P78325-3
	ADAM8	NM_001164490.2		c.2049G>C	p.Pro683Pro	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.2077G>C	p.Ala693Pro	missense	Exon 19 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.2244G>C	p.Pro748Pro	synonymous	Exon 20 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000897047.1		c.2238G>C	p.Pro746Pro	synonymous	Exon 20 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1107656 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 524476

African (AFR) AF: 0.00 AC: 0 AN: 23382

American (AMR) AF: 0.00 AC: 0 AN: 11030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14470

East Asian (EAS) AF: 0.00 AC: 0 AN: 27174

South Asian (SAS) AF: 0.00 AC: 0 AN: 21224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3016

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 928272

Other (OTH) AF: 0.00 AC: 0 AN: 44310

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41450

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

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

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.055
DANN	Benign	0.93
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.081	T
PhyloP100		-7.5
PROVEAN	Benign	1.1	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	T
Vest4		0.20
MVP		0.56
GERP RS		-7.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1483847365; hg19: chr10-135081442;