rs200839167

Variant names:

• chr8-24320275-A-G
• rs200839167
• NM_014265.6:c.616A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014265.6(ADAM28):​c.616A>G​(p.Ile206Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,603,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I206T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: ADAM28 NM_014265.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0830
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032110333).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014265.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM28	NM_014265.6	MANE Select	c.616A>G	p.Ile206Val	missense	Exon 7 of 23	NP_055080.2	Q9UKQ2-1
	ADAM28	NM_001304351.2		c.616A>G	p.Ile206Val	missense	Exon 7 of 22	NP_001291280.1
	ADAM28	NM_021777.5		c.616A>G	p.Ile206Val	missense	Exon 7 of 14	NP_068547.2	Q9UKQ2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM28	ENST00000265769.9	TSL:1 MANE Select	c.616A>G	p.Ile206Val	missense	Exon 7 of 23	ENSP00000265769.4	Q9UKQ2-1
	ADAM28	ENST00000437154.6	TSL:1	c.616A>G	p.Ile206Val	missense	Exon 7 of 14	ENSP00000393699.2	Q9UKQ2-2
	ADAM28	ENST00000699027.1		c.616A>G	p.Ile206Val	missense	Exon 7 of 24	ENSP00000514095.1	A0A8V8TMM6

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000282 AC: 70 AN: 248116 AF XY: 0.000231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000173 AC: 251 AN: 1451786 Hom.: 1 Cov.: 28 AF XY: 0.000202 AC XY: 146 AN XY: 722674

African (AFR) AF: 0.0000303 AC: 1 AN: 33050

American (AMR) AF: 0.000248 AC: 11 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.00200 AC: 52 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39424

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85514

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.000158 AC: 174 AN: 1104532

Other (OTH) AF: 0.000167 AC: 10 AN: 59952

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74240

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000297 AC: 36

EpiCase AF: 0.000494

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.5
DANN	Benign	0.91
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.040	N
PhyloP100		0.083
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.065
Sift	Benign	0.32	T
Sift4G	Benign	0.36	T
Polyphen		0.020	B
Vest4		0.15
MVP		0.45
MPC		0.038
ClinPred		0.69	D
GERP RS		1.7
Varity_R		0.060
gMVP		0.45
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200839167; hg19: chr8-24177788;