10-133268059-C-A

Position:

• chr10-133268059-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001109.5(ADAM8):​c.2123G>T​(p.Ser708Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000269 in 1,116,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.26

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11668253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM8	NM_001109.5	c.2123G>T	p.Ser708Ile	missense_variant	20/23	ENST00000445355.8	NP_001100.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM8	ENST00000445355.8	c.2123G>T	p.Ser708Ile	missense_variant	20/23	1	NM_001109.5	ENSP00000453302.1
ADAM8	ENST00000415217.7	c.1956G>T	p.Gln652His	missense_variant	19/22	1		ENSP00000453855.1
ADAM8	ENST00000485491.6	c.1928G>T	p.Ser643Ile	missense_variant	18/20	2		ENSP00000453043.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000269 AC: 3 AN: 1116608 Hom.: 0 Cov.: 32 AF XY: 0.00000567 AC XY: 3 AN XY: 529464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000322

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.2123G>T (p.S708I) alteration is located in exon 20 (coding exon 20) of the ADAM8 gene. This alteration results from a G to T substitution at nucleotide position 2123, causing the serine (S) at amino acid position 708 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.90
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.12	T
PROVEAN	Benign	-0.65	N
Sift	Benign	0.096	T
Sift4G	Benign	0.13	T
Vest4		0.16
MVP		0.57
GERP RS		1.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1846386486; hg19: chr10-135081563;