8-24330036-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014265.6(ADAM28):ā€‹c.1024G>Cā€‹(p.Gly342Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

ADAM28
NM_014265.6 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.04
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)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAM28NM_014265.6 linkuse as main transcriptc.1024G>C p.Gly342Arg missense_variant 11/23 ENST00000265769.9 NP_055080.2
ADAM7-AS1NR_125808.1 linkuse as main transcriptn.502-29107C>G 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.1024G>C p.Gly342Arg missense_variant 11/231 NM_014265.6 ENSP00000265769 A2Q9UKQ2-1
ADAM7-AS1ENST00000519689.1 linkuse as main transcriptn.607-29107C>G intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251336
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135848
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461470
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727046
show subpopulations
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000378

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 GeneticsJun 06, 2023The c.1024G>C (p.G342R) alteration is located in exon 11 (coding exon 11) of the ADAM28 gene. This alteration results from a G to C substitution at nucleotide position 1024, causing the glycine (G) at amino acid position 342 to be replaced by an arginine (R). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.42
T;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.068
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.16
D
MutationAssessor
Pathogenic
4.3
H;H
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-7.6
D;D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.97
MutPred
0.94
Gain of methylation at G342 (P = 0.0274);Gain of methylation at G342 (P = 0.0274);
MVP
0.86
MPC
0.30
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.97
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1324560118; hg19: chr8-24187549; API