8-24491934-C-A

Position:

• chr8-24491934-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000175238.10(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. 13/21 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 ENST00000175238.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.268

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM7	NM_003817.4	c.1388C>A	p.Ala463Glu	missense_variant	14/22	ENST00000175238.10	NP_003808.2
ADAM7-AS2	NR_125809.1	n.673G>T		non_coding_transcript_exon_variant	4/5
ADAM7-AS1	NR_125808.1	n.79+56606G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM7	ENST00000175238.10	c.1388C>A	p.Ala463Glu	missense_variant	14/22	1	NM_003817.4	ENSP00000175238.5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.1388C>A (p.A463E) alteration is located in exon 14 (coding exon 14) of the ADAM7 gene. This alteration results from a C to A substitution at nucleotide position 1388, causing the alanine (A) at amino acid position 463 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.96	D;.;D
Vest4		0.27
MutPred		0.62		Loss of catalytic residue at A463 (P = 0.093);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1173589877; hg19: chr8-24349447;