NM_001109.5:c.2458G>A

Variant names:

• chr10-133263173-C-T
• rs561363568
• NM_001109.5:c.2458G>A

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.2458G>A​(p.Ala820Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A820V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.249
• 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=0.108861625).

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.2458G>A	p.Ala820Thr	missense	Exon 23 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164490.2		c.2185G>A	p.Ala729Thr	missense	Exon 20 of 20	NP_001157962.1	P78325-2
	ADAM8	NM_001164489.2		c.*62G>A		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.2458G>A	p.Ala820Thr	missense	Exon 23 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000415217.7	TSL:1	c.*62G>A		3_prime_UTR	Exon 22 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000897047.1		c.2452G>A	p.Ala818Thr	missense	Exon 23 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250544 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461532 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111800

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 35

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.075
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	T
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.00090	T
MetaRNN	Benign	0.11	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.25
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.81	N
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.12
MVP		0.41
MPC		0.22
GERP RS		-0.70
Varity_R		0.077
gMVP		0.057
Mutation Taster		=99/1	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: rs561363568; hg19: chr10-135076677; COSMIC: COSV105344520;