NM_003817.4:c.1774A>C

Variant names:

• chr8-24493161-A-C
• rs762614916
• NM_003817.4:c.1774A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003817.4(ADAM7):​c.1774A>C​(p.Ile592Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM7 NM_003817.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

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

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=0.0681164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003817.4. 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
	ADAM7	NM_003817.4	MANE Select	c.1774A>C	p.Ile592Leu	missense	Exon 16 of 22	NP_003808.2	A0A384MTL6
	ADAM7-AS1	NR_125808.1		n.79+55379T>G		intron	N/A
	ADAM7-AS2	NR_125809.1		n.447-1001T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM7	ENST00000175238.10	TSL:1 MANE Select	c.1774A>C	p.Ile592Leu	missense	Exon 16 of 22	ENSP00000175238.5	Q9H2U9-1
	ADAM7	ENST00000520720.1	TSL:1	c.1090A>C	p.Ile364Leu	missense	Exon 10 of 15	ENSP00000430400.1	E5RK87
	ADAM7	ENST00000380789.5	TSL:5	c.1774A>C	p.Ile592Leu	missense	Exon 16 of 23	ENSP00000370166.1	C9JK28

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249622 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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	0.093
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.5
DANN	Benign	0.90
DEOGEN2	Benign	0.00065	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.91	L
PhyloP100		1.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.041
Sift	Benign	0.24	T
Sift4G	Benign	0.15	T
Polyphen		0.0060	B
Vest4		0.13
MutPred		0.66		Gain of catalytic residue at I592 (P = 0.0967)
MVP		0.21
MPC		0.048
ClinPred		0.074	T
GERP RS		1.9
Varity_R		0.054
gMVP		0.63
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs762614916; hg19: chr8-24350674;