chr8-24349925-G-A

Position:

• chr8-24349925-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014265.6(ADAM28):​c.2052G>A​(p.Met684Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,246 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.054 (316 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1664 hom.)
• Consequence: ADAM28 NM_014265.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210

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]

ADAM28 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014255345).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM28	NM_014265.6	c.2052G>A	p.Met684Ile	missense_variant	19/23	ENST00000265769.9	NP_055080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM28	ENST00000265769.9	c.2052G>A	p.Met684Ile	missense_variant	19/23	1	NM_014265.6	ENSP00000265769.4

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8121 AN: 151972 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0974

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0436

GnomAD3 exomes AF: 0.0466 AC: 11704 AN: 251202 Hom.: 458 AF XY: 0.0470 AC XY: 6386 AN XY: 135744

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0333

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0972

Gnomad FIN exome AF: 0.0319

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0318

GnomAD4 exome AF: 0.0375 AC: 54748 AN: 1461156 Hom.: 1664 Cov.: 30 AF XY: 0.0388 AC XY: 28226 AN XY: 726856

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0333

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.0944

Gnomad4 FIN exome AF: 0.0314

Gnomad4 NFE exome AF: 0.0288

Gnomad4 OTH exome AF: 0.0387

GnomAD4 genome AF: 0.0536 AC: 8151 AN: 152090 Hom.: 316 Cov.: 32 AF XY: 0.0538 AC XY: 4001 AN XY: 74324

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.0963

Gnomad4 FIN AF: 0.0321

Gnomad4 NFE AF: 0.0284

Gnomad4 OTH AF: 0.0446

Alfa AF: 0.0338 Hom.: 320

Bravo AF: 0.0548

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.101 AC: 443

ESP6500EA AF: 0.0276 AC: 237

ExAC AF: 0.0490 AC: 5945

Asia WGS AF: 0.117 AC: 404 AN: 3478

EpiCase AF: 0.0237

EpiControl AF: 0.0237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.3
DANN	Benign	0.53
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.42		Loss of sheet (P = 7e-04);
MPC		0.040
ClinPred		0.0023	T
GERP RS		-0.58
Varity_R		0.032
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs7829965; hg19: chr8-24207438; COSMIC: COSV56101013; COSMIC: COSV56101013;