10-133268842-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001109.5(ADAM8):​c.1969T>C​(p.Phe657Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,608,346 control chromosomes in the GnomAD database, including 601,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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: 𝑓 0.82 (51270 hom., cov: 36)
  • Exomes 𝑓: 0.87 (550501 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0698731E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM8	NM_001109.5	MANE Select	c.1969T>C	p.Phe657Leu	missense	Exon 19 of 23	NP_001100.3
	ADAM8	NM_001164490.2		c.1774T>C	p.Phe592Leu	missense	Exon 17 of 20	NP_001157962.1
	ADAM8	NM_001164489.2		c.1948+603T>C		intron	N/A	NP_001157961.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.1969T>C	p.Phe657Leu	missense	Exon 19 of 23	ENSP00000453302.1
	ADAM8	ENST00000415217.7	TSL:1	c.1948+603T>C		intron	N/A	ENSP00000453855.1
	ADAM8	ENST00000485491.6	TSL:2	c.1774T>C	p.Phe592Leu	missense	Exon 17 of 20	ENSP00000453043.1

Frequencies

GnomAD3 genomes AF: 0.815 AC: 124077 AN: 152150 Hom.: 51238 Cov.: 36

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.877

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.822

Gnomad NFE AF: 0.871

Gnomad OTH AF: 0.827

GnomAD2 exomes AF: 0.860 AC: 210629 AN: 244854 AF XY: 0.866

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 0.957

Gnomad FIN exome AF: 0.906

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.875

GnomAD4 exome AF: 0.868 AC: 1264469 AN: 1456076 Hom.: 550501 Cov.: 84 AF XY: 0.870 AC XY: 630235 AN XY: 724612

African (AFR) AF: 0.666 AC: 22302 AN: 33470

American (AMR) AF: 0.794 AC: 35419 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 23566 AN: 26114

East Asian (EAS) AF: 0.936 AC: 37121 AN: 39680

South Asian (SAS) AF: 0.880 AC: 75848 AN: 86212

European-Finnish (FIN) AF: 0.905 AC: 43610 AN: 48184

Middle Eastern (MID) AF: 0.861 AC: 4963 AN: 5764

European-Non Finnish (NFE) AF: 0.872 AC: 969761 AN: 1111714

Other (OTH) AF: 0.860 AC: 51879 AN: 60320

GnomAD4 genome AF: 0.815 AC: 124158 AN: 152270 Hom.: 51270 Cov.: 36 AF XY: 0.819 AC XY: 61002 AN XY: 74456

African (AFR) AF: 0.672 AC: 27920 AN: 41536

American (AMR) AF: 0.808 AC: 12372 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 3142 AN: 3472

East Asian (EAS) AF: 0.943 AC: 4883 AN: 5176

South Asian (SAS) AF: 0.877 AC: 4236 AN: 4828

European-Finnish (FIN) AF: 0.909 AC: 9659 AN: 10622

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.871 AC: 59234 AN: 68014

Other (OTH) AF: 0.829 AC: 1746 AN: 2106

Alfa AF: 0.856 Hom.: 194725

Bravo AF: 0.801

TwinsUK AF: 0.875 AC: 3246

ALSPAC AF: 0.877 AC: 3381

ESP6500AA AF: 0.674 AC: 2966

ESP6500EA AF: 0.866 AC: 7447

ExAC AF: 0.859 AC: 103914

Asia WGS AF: 0.890 AC: 3096 AN: 3478

EpiCase AF: 0.871

EpiControl AF: 0.867

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.060
DANN	Benign	0.22
DEOGEN2	Benign	0.041	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000011	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.83
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.27	N
Sift	Benign	0.65	T
Sift4G	Benign	0.65	T
Vest4		0.032
MPC		0.14
GERP RS		-7.1
Varity_R		0.019
gMVP		0.27
Mutation Taster		=97/3	polymorphism (auto)

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; COSMIC: COSV69864593; COSMIC: COSV69864593;