NM_001464.5:c.1621C>T

Variant names:

• chr8-39755904-G-A
• rs1484843970
• NM_001464.5:c.1621C>T

Variant summary

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

The NM_001464.5(ADAM2):​c.1621C>T​(p.Gln541*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000752 in 1,330,362 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ADAM2 NM_001464.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5	c.1621C>T	p.Gln541*	stop_gained	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.1621C>T	p.Gln541*	stop_gained	Exon 16 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1564C>T	p.Gln522*	stop_gained	Exon 15 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1236-83C>T		intron_variant	Intron 11 of 16	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1608+5277C>T		intron_variant	Intron 15 of 19	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 233826 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.52e-7 AC: 1 AN: 1330362 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 666288

African (AFR) AF: 0.00 AC: 0 AN: 29900

American (AMR) AF: 0.0000251 AC: 1 AN: 39864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.00 AC: 0 AN: 38384

South Asian (SAS) AF: 0.00 AC: 0 AN: 76850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4258

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1007658

Other (OTH) AF: 0.00 AC: 0 AN: 55734

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Benign	0.94
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.024	N
PhyloP100		-1.1
Vest4		0.70
GERP RS		-6.1
Mutation Taster		=134/66	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1484843970; hg19: chr8-39613423;