10-133268059-C-A

Variant names:

• chr10-133268059-C-A
• rs1846386486
• NM_001109.5:c.2123G>T

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.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. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• 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=0.11668253).

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.2123G>T	p.Ser708Ile	missense	Exon 20 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164489.2		c.1956G>T	p.Gln652His	missense	Exon 19 of 22	NP_001157961.1	P78325-3
	ADAM8	NM_001164490.2		c.1928G>T	p.Ser643Ile	missense	Exon 18 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.2123G>T	p.Ser708Ile	missense	Exon 20 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000415217.7	TSL:1	c.1956G>T	p.Gln652His	missense	Exon 19 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000897047.1		c.2117G>T	p.Ser706Ile	missense	Exon 20 of 23	ENSP00000567106.1

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

African (AFR) AF: 0.00 AC: 0 AN: 23954

American (AMR) AF: 0.00 AC: 0 AN: 11510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14578

East Asian (EAS) AF: 0.00 AC: 0 AN: 28016

South Asian (SAS) AF: 0.00 AC: 0 AN: 21248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4250

European-Non Finnish (NFE) AF: 0.00000322 AC: 3 AN: 932174

Other (OTH) AF: 0.00 AC: 0 AN: 44638

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.13
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
PhyloP100		-3.3
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
Varity_R		0.092
Mutation Taster		=100/0	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: rs1846386486; hg19: chr10-135081563;