8-24499305-A-C

Variant names:

• chr8-24499305-A-C
• rs13259668
• NM_003817.4:c.1912A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003817.4(ADAM7):​c.1912A>C​(p.Asn638His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,597,378 control chromosomes in the GnomAD database, including 87,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (8393 hom., cov: 32)
  • Exomes 𝑓: 0.33 (79202 hom.)
• Consequence: ADAM7 NM_003817.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55

Genes affected

ADAM7 (HGNC:214): (ADAM metallopeptidase domain 7) This gene encodes a member of the ADAMs family of zinc proteases. These transmembrane proteins play roles in multiple processes including cell signaling, adhesion and migration. The encoded protein lacks protease activity and may play roles in protein-protein interactions and cell adhesion processes including sperm-egg fusion. Mutations in this gene may be involved in the progression of melanoma. [provided by RefSeq, Oct 2011]

ADAM7-AS2 (HGNC:56153): (ADAM7 antisense RNA 2)

ADAM7-AS1 (HGNC:56152): (ADAM7, ADAMDEC1 and ADAM28 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.763491E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM7	NM_003817.4	c.1912A>C	p.Asn638His	missense_variant	Exon 17 of 22	ENST00000175238.10	NP_003808.2
ADAM7-AS1	NR_125808.1	n.79+49235T>G		intron_variant	Intron 1 of 5
ADAM7-AS2	NR_125809.1	n.447-7145T>G		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM7	ENST00000175238.10	c.1912A>C	p.Asn638His	missense_variant	Exon 17 of 22	1	NM_003817.4	ENSP00000175238.5

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49859 AN: 151814 Hom.: 8377 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.331

GnomAD3 exomes AF: 0.345 AC: 82754 AN: 240074 Hom.: 15154 AF XY: 0.344 AC XY: 44783 AN XY: 130008

Gnomad AFR exome AF: 0.325

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.187

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.327 AC: 472766 AN: 1445446 Hom.: 79202 Cov.: 31 AF XY: 0.330 AC XY: 237015 AN XY: 719016

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.437

Gnomad4 EAS exome AF: 0.229

Gnomad4 SAS exome AF: 0.414

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.329 AC: 49914 AN: 151932 Hom.: 8393 Cov.: 32 AF XY: 0.332 AC XY: 24613 AN XY: 74242

Gnomad4 AFR AF: 0.330

Gnomad4 AMR AF: 0.393

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.329

Alfa AF: 0.324 Hom.: 16510

Bravo AF: 0.333

TwinsUK AF: 0.319 AC: 1181

ALSPAC AF: 0.304 AC: 1173

ESP6500AA AF: 0.325 AC: 1430

ESP6500EA AF: 0.333 AC: 2868

ExAC AF: 0.342 AC: 41550

Asia WGS AF: 0.315 AC: 1096 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.15
DANN	Benign	0.37
DEOGEN2	Benign	0.0014	T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.067	T;T;T
MetaRNN	Benign	0.000078	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.85	L;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.0060
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.11
MPC		0.049
ClinPred		0.0037	T
GERP RS		-4.4
Varity_R		0.044
gMVP		0.74

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: rs13259668; hg19: chr8-24356818; COSMIC: COSV51539527;