NM_001109.5:c.1969T>G

Variant names:

• chr10-133268842-A-C
• rs2275720
• NM_001109.5:c.1969T>G

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.1969T>G​(p.Phe657Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,188 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.831
• Publications: 30 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=0.06814554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM8	NM_001109.5	c.1969T>G	p.Phe657Val	missense_variant	Exon 19 of 23	ENST00000445355.8	NP_001100.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM8	ENST00000445355.8	c.1969T>G	p.Phe657Val	missense_variant	Exon 19 of 23	1	NM_001109.5	ENSP00000453302.1
ADAM8	ENST00000415217.7	c.1948+603T>G		intron_variant	Intron 18 of 21	1		ENSP00000453855.1
ADAM8	ENST00000485491.6	c.1774T>G	p.Phe592Val	missense_variant	Exon 17 of 20	2		ENSP00000453043.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456188 Hom.: 0 Cov.: 84 AF XY: 0.00 AC XY: 0 AN XY: 724660

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.034
DANN	Benign	0.27
DEOGEN2	Benign	0.032	T;.
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.17	T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.068	T;T
MutationAssessor	Benign	0.69	N;.
PhyloP100		-0.83
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.33	N;N
Sift	Benign	0.50	T;T
Sift4G	Benign	0.51	T;T
Vest4		0.093
MVP		0.56
MPC		0.16
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.33
Mutation Taster		=97/3	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: rs2275720; hg19: chr10-135082346;