8-24313543-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014265.6(ADAM28):ā€‹c.539T>Gā€‹(p.Leu180Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00013 ( 0 hom., cov: 32)
Exomes š‘“: 0.00020 ( 0 hom. )

Consequence

ADAM28
NM_014265.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.130
Variant links:
Genes affected
ADAM28 (HGNC:206): (ADAM metallopeptidase domain 28) 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 protein encoded by this gene is a lymphocyte-expressed ADAM protein. This gene is present in a gene cluster with other members of the ADAM family on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]
ADAM7-AS1 (HGNC:56152): (ADAM7, ADAMDEC1 and ADAM28 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.10009536).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAM28NM_014265.6 linkuse as main transcriptc.539T>G p.Leu180Trp missense_variant 6/23 ENST00000265769.9 NP_055080.2
ADAM7-AS1NR_125808.1 linkuse as main transcriptn.502-12614A>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAM28ENST00000265769.9 linkuse as main transcriptc.539T>G p.Leu180Trp missense_variant 6/231 NM_014265.6 ENSP00000265769 A2Q9UKQ2-1
ADAM7-AS1ENST00000519689.1 linkuse as main transcriptn.607-12614A>C intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000203
AC:
51
AN:
251100
Hom.:
0
AF XY:
0.000214
AC XY:
29
AN XY:
135714
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000261
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000335
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000205
AC:
299
AN:
1461504
Hom.:
0
Cov.:
31
AF XY:
0.000215
AC XY:
156
AN XY:
727052
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.000254
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000228
Hom.:
0
Bravo
AF:
0.000144
ExAC
AF:
0.000247
AC:
30
EpiCase
AF:
0.000437
EpiControl
AF:
0.000357

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 28, 2024The c.539T>G (p.L180W) alteration is located in exon 6 (coding exon 6) of the ADAM28 gene. This alteration results from a T to G substitution at nucleotide position 539, causing the leucine (L) at amino acid position 180 to be replaced by a tryptophan (W). 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
0.090
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
6.3
DANN
Benign
0.90
DEOGEN2
Benign
0.016
T;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.052
N
LIST_S2
Benign
0.35
T;T
M_CAP
Benign
0.0088
T
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
0.55
N;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.38
N;N
REVEL
Benign
0.10
Sift
Benign
0.18
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.95
P;D
Vest4
0.25
MVP
0.56
MPC
0.10
ClinPred
0.015
T
GERP RS
0.75
Varity_R
0.028
gMVP
0.47

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147092030; hg19: chr8-24171056; API