10-133263190-C-G

Variant names:

• chr10-133263190-C-G
• rs760526884
• NM_001109.5:c.2441G>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.2441G>C​(p.Arg814Thr) 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. 13/18 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. R814K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 35)
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• Publications: 5 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=0.11727691).

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.2441G>C	p.Arg814Thr	missense	Exon 23 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164490.2		c.2168G>C	p.Arg723Thr	missense	Exon 20 of 20	NP_001157962.1	P78325-2
	ADAM8	NM_001164489.2		c.*45G>C		3_prime_UTR	Exon 22 of 22	NP_001157961.1	P78325-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.2441G>C	p.Arg814Thr	missense	Exon 23 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000415217.7	TSL:1	c.*45G>C		3_prime_UTR	Exon 22 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000897047.1		c.2435G>C	p.Arg812Thr	missense	Exon 23 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.12	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.23
MVP		0.46
MPC		0.63
GERP RS		2.3
Varity_R		0.067
gMVP		0.11
Mutation Taster		=91/9	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: rs760526884; hg19: chr10-135076694;