8-39755863-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0230

Publications

0 publications found
Variant links:
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]

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ACMG classification

Classification was made for transcript

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=0.23120803).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAM2NM_001464.5 linkc.1662A>C p.Leu554Phe missense_variant Exon 16 of 21 ENST00000265708.9 NP_001455.3 Q99965-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAM2ENST00000265708.9 linkc.1662A>C p.Leu554Phe missense_variant Exon 16 of 21 1 NM_001464.5 ENSP00000265708.4 Q99965-1
ADAM2ENST00000347580.8 linkc.1605A>C p.Leu535Phe missense_variant Exon 15 of 20 1 ENSP00000343854.4 Q99965-2
ADAM2ENST00000379853.6 linkc.1236-42A>C intron_variant Intron 11 of 16 1 ENSP00000369182.2 Q6P2G0
ADAM2ENST00000521880.5 linkc.1608+5318A>C intron_variant Intron 15 of 19 2 ENSP00000429352.1 B4DWY7

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
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32964
American (AMR)
AF:
0.00
AC:
0
AN:
44446
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25996
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39476
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85052
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53386
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5510
European-Non Finnish (NFE)
AF:
0.0000110
AC:
12
AN:
1093176
Other (OTH)
AF:
0.00
AC:
0
AN:
59654
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
LINK: link

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
PhyloP100
0.023
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
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs1312394249; hg19: chr8-39613382; API