10-133267368-C-T

Variant names:

• chr10-133267368-C-T
• rs376925289
• NM_001109.5:c.2303G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001109.5(ADAM8):​c.2303G>A​(p.Arg768Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,609,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.81
• Publications: 0 publications found

Genes affected

ADAM8 (HGNC:215): (ADAM metallopeptidase domain 8) 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 may be involved in cell adhesion during neurodegeneration, and it is thought to be a target for allergic respiratory diseases, including asthma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029115647).
• BP6: Variant 10-133267368-C-T is Benign according to our data. Variant chr10-133267368-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3146135.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109.5. 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
	ADAM8	NM_001109.5	MANE Select	c.2303G>A	p.Arg768Gln	missense	Exon 21 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164490.2		c.2108G>A	p.Arg703Gln	missense	Exon 19 of 20	NP_001157962.1	P78325-2
	ADAM8	NM_001164489.2		c.2136G>A	p.Pro712Pro	synonymous	Exon 20 of 22	NP_001157961.1	P78325-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.2303G>A	p.Arg768Gln	missense	Exon 21 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000415217.7	TSL:1	c.2136G>A	p.Pro712Pro	synonymous	Exon 20 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000897047.1		c.2297G>A	p.Arg766Gln	missense	Exon 21 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000706 AC: 17 AN: 240926 AF XY: 0.0000461

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000150 AC: 218 AN: 1457362 Hom.: 0 Cov.: 31 AF XY: 0.000141 AC XY: 102 AN XY: 724446

African (AFR) AF: 0.000239 AC: 8 AN: 33470

American (AMR) AF: 0.0000454 AC: 2 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.0000706 AC: 6 AN: 84984

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000176 AC: 195 AN: 1110834

Other (OTH) AF: 0.0000995 AC: 6 AN: 60274

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15304

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: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

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

Alfa AF: 0.000161 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000116 AC: 14

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.022
DANN	Benign	0.56
DEOGEN2	Benign	0.030	T
FATHMM_MKL	Benign	0.00061	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.029	T
PhyloP100		-2.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.54	N
Sift	Benign	0.47	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.50
MPC		0.14
GERP RS		-6.0
Varity_R		0.016
gMVP		0.048
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376925289; hg19: chr10-135080872;