NM_014265.6:c.251C>T

Variant names:

• chr8-24310186-C-T
• rs372777278
• NM_014265.6:c.251C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014265.6(ADAM28):​c.251C>T​(p.Thr84Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: ADAM28 NM_014265.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.311
• Publications: 1 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15923333).

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.251C>T	p.Thr84Met	missense	Exon 4 of 23	NP_055080.2	Q9UKQ2-1
	ADAM28	NM_001304351.2		c.251C>T	p.Thr84Met	missense	Exon 4 of 22	NP_001291280.1
	ADAM28	NM_021777.5		c.251C>T	p.Thr84Met	missense	Exon 4 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.251C>T	p.Thr84Met	missense	Exon 4 of 23	ENSP00000265769.4	Q9UKQ2-1
	ADAM28	ENST00000437154.6	TSL:1	c.251C>T	p.Thr84Met	missense	Exon 4 of 14	ENSP00000393699.2	Q9UKQ2-2
	ADAM28	ENST00000699027.1		c.251C>T	p.Thr84Met	missense	Exon 4 of 24	ENSP00000514095.1	A0A8V8TMM6

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152066 Hom.: 0 Cov.: 32

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250854 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 106 AN: 1461160 Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50 AN XY: 726878

African (AFR) AF: 0.0000598 AC: 2 AN: 33440

American (AMR) AF: 0.000202 AC: 9 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000837 AC: 93 AN: 1111548

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74406

African (AFR) AF: 0.0000482 AC: 2 AN: 41530

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

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	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.31
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.047
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.36	B
Vest4		0.19
MVP		0.35
MPC		0.051
ClinPred		0.15	T
GERP RS		2.1
Varity_R		0.058
gMVP		0.48
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs372777278; hg19: chr8-24167699; COSMIC: COSV99738905;