8-39755863-T-G

Variant names:

• chr8-39755863-T-G
• rs1312394249
• NM_001464.5:c.1662A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001464.5(ADAM2):​c.1662A>C​(p.Leu554Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000834 in 1,439,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0230

Genes affected

ADAM2 (HGNC:198): (ADAM metallopeptidase domain 2) 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 encoded protein is a subunit of an integral sperm membrane glycoprotein called fertilin, which plays an important role in sperm-egg interactions. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23120803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5	c.1662A>C	p.Leu554Phe	missense_variant	Exon 16 of 21	ENST00000265708.9	NP_001455.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM2	ENST00000265708.9	c.1662A>C	p.Leu554Phe	missense_variant	Exon 16 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1605A>C	p.Leu535Phe	missense_variant	Exon 15 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1236-42A>C		intron_variant	Intron 11 of 16	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1608+5318A>C		intron_variant	Intron 15 of 19	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000834 AC: 12 AN: 1439660 Hom.: 0 Cov.: 27 AF XY: 0.00000976 AC XY: 7 AN XY: 717376

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: 0.0000110

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1662A>C (p.L554F) alteration is located in exon 16 (coding exon 16) of the ADAM2 gene. This alteration results from a A to C substitution at nucleotide position 1662, causing the leucine (L) at amino acid position 554 to be replaced by a phenylalanine (F). 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	0.25
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.061
Sift	Benign	0.14	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.30	B;B
Vest4		0.18
MutPred		0.67		.;Loss of ubiquitination at K552 (P = 0.0853);
MVP		0.19
MPC		0.058
ClinPred		0.16	T
GERP RS		2.0
Varity_R		0.089
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1312394249; hg19: chr8-39613382;