8-24294187-C-G

Variant names:

• chr8-24294187-C-G
• rs761990099
• NM_014265.6:c.38C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014265.6(ADAM28):​c.38C>G​(p.Ser13Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S13F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADAM28 NM_014265.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.38C>G	p.Ser13Cys	missense	Exon 1 of 23	NP_055080.2	Q9UKQ2-1
	ADAM28	NM_001304351.2		c.38C>G	p.Ser13Cys	missense	Exon 1 of 22	NP_001291280.1
	ADAM28	NM_021777.5		c.38C>G	p.Ser13Cys	missense	Exon 1 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.38C>G	p.Ser13Cys	missense	Exon 1 of 23	ENSP00000265769.4	Q9UKQ2-1
	ADAM28	ENST00000437154.6	TSL:1	c.38C>G	p.Ser13Cys	missense	Exon 1 of 14	ENSP00000393699.2	Q9UKQ2-2
	ADAM28	ENST00000699027.1		c.38C>G	p.Ser13Cys	missense	Exon 1 of 24	ENSP00000514095.1	A0A8V8TMM6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251378 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0022	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.18	T
Polyphen		0.97	D
Vest4		0.44
MutPred		0.74		Loss of helix (P = 0.0033)
MVP		0.36
MPC		0.17
ClinPred		0.41	T
GERP RS		3.7
PromoterAI		-0.012	Neutral
Varity_R		0.12
gMVP		0.71
Mutation Taster		=86/14	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: rs761990099; hg19: chr8-24151700;