8-24323991-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014265.6(ADAM28):​c.878C>T​(p.Ala293Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000993 in 1,611,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ADAM28
NM_014265.6 missense

Scores

2
12
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAM28NM_014265.6 linkuse as main transcriptc.878C>T p.Ala293Val missense_variant 9/23 ENST00000265769.9 NP_055080.2
ADAM7-AS1NR_125808.1 linkuse as main transcriptn.502-23062G>A 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.878C>T p.Ala293Val missense_variant 9/231 NM_014265.6 ENSP00000265769 A2Q9UKQ2-1
ADAM7-AS1ENST00000519689.1 linkuse as main transcriptn.607-23062G>A intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000659
AC:
10
AN:
151858
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000218
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249944
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135066
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
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:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1459618
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726124
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
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
AF:
0.0000659
AC:
10
AN:
151858
Hom.:
0
Cov.:
32
AF XY:
0.0000674
AC XY:
5
AN XY:
74144
show subpopulations
Gnomad4 AFR
AF:
0.000218
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000494
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000165
AC:
2

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 GeneticsApr 13, 2022The c.878C>T (p.A293V) alteration is located in exon 9 (coding exon 9) of the ADAM28 gene. This alteration results from a C to T substitution at nucleotide position 878, causing the alanine (A) at amino acid position 293 to be replaced by a valine (V). 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
0.34
BayesDel_addAF
Uncertain
0.033
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.18
T;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.87
D;T
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Uncertain
-0.079
T
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Uncertain
0.50
Sift
Uncertain
0.0010
D;D
Sift4G
Benign
0.11
T;D
Polyphen
1.0
D;P
Vest4
0.86
MVP
0.78
MPC
0.28
ClinPred
0.93
D
GERP RS
5.4
Varity_R
0.50
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs369442825; hg19: chr8-24181504; API