8-24491934-C-A

Variant names:

• chr8-24491934-C-A
• rs1173589877
• NM_003817.4:c.1388C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003817.4(ADAM7):​c.1388C>A​(p.Ala463Glu) 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 1,460,420 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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)
  • Exomes 𝑓: 0.0000021 (1 hom.)
• Consequence: ADAM7 NM_003817.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.268
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30635166).

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.1388C>A	p.Ala463Glu	missense	Exon 14 of 22	NP_003808.2	A0A384MTL6
	ADAM7-AS2	NR_125809.1		n.673G>T		non_coding_transcript_exon	Exon 4 of 5
	ADAM7-AS1	NR_125808.1		n.79+56606G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM7	ENST00000175238.10	TSL:1 MANE Select	c.1388C>A	p.Ala463Glu	missense	Exon 14 of 22	ENSP00000175238.5	Q9H2U9-1
	ADAM7	ENST00000520720.1	TSL:1	c.704C>A	p.Ala235Glu	missense	Exon 8 of 15	ENSP00000430400.1	E5RK87
	ADAM7	ENST00000380789.5	TSL:5	c.1388C>A	p.Ala463Glu	missense	Exon 14 of 23	ENSP00000370166.1	C9JK28

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460420 Hom.: 1 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726464

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111334

Other (OTH) AF: 0.00 AC: 0 AN: 60326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.27
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.024	D
Polyphen		0.96	D
Vest4		0.27
MutPred		0.62		Loss of catalytic residue at A463 (P = 0.093)
MVP		0.49
MPC		0.30
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.52
gMVP		0.66
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1173589877; hg19: chr8-24349447;