10-133267399-T-G

Variant names:

• chr10-133267399-T-G
• rs1033597620
• NM_001109.5:c.2272A>C

Variant summary

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

The NM_001109.5(ADAM8):​c.2272A>C​(p.Ser758Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S758C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108
• 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=0.21080956).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109.5. 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.2272A>C	p.Ser758Arg	missense	Exon 21 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164489.2		c.2105A>C	p.Gln702Pro	missense	Exon 20 of 22	NP_001157961.1	P78325-3
	ADAM8	NM_001164490.2		c.2077A>C	p.Ser693Arg	missense	Exon 19 of 20	NP_001157962.1	P78325-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.2272A>C	p.Ser758Arg	missense	Exon 21 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000415217.7	TSL:1	c.2105A>C	p.Gln702Pro	missense	Exon 20 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000897047.1		c.2266A>C	p.Ser756Arg	missense	Exon 21 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.78
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.21	T
PhyloP100		-0.11
PROVEAN	Benign	0.63	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.30	T
Vest4		0.45
MVP		0.55
GERP RS		1.2
Varity_R		0.051
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1033597620; hg19: chr10-135080903;