NM_001109.5:c.2203C>T

Variant names:

• chr10-133267979-G-A
• rs1846380159
• NM_001109.5:c.2203C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001109.5(ADAM8):​c.2203C>T​(p.Pro735Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,242 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.224
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105774045).

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.2203C>T	p.Pro735Ser	missense	Exon 20 of 23	NP_001100.3	P78325-1
	ADAM8	NM_001164489.2		c.2036C>T	p.Ala679Val	missense	Exon 19 of 22	NP_001157961.1	P78325-3
	ADAM8	NM_001164490.2		c.2008C>T	p.Pro670Ser	missense	Exon 18 of 20	NP_001157962.1	P78325-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.2203C>T	p.Pro735Ser	missense	Exon 20 of 23	ENSP00000453302.1	P78325-1
	ADAM8	ENST00000415217.7	TSL:1	c.2036C>T	p.Ala679Val	missense	Exon 19 of 22	ENSP00000453855.1	P78325-3
	ADAM8	ENST00000897047.1		c.2197C>T	p.Pro733Ser	missense	Exon 20 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152242 Hom.: 1 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: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1108626 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 525026

African (AFR) AF: 0.00 AC: 0 AN: 23502

American (AMR) AF: 0.00 AC: 0 AN: 10808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14478

East Asian (EAS) AF: 0.00 AC: 0 AN: 27230

South Asian (SAS) AF: 0.00 AC: 0 AN: 20928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 928344

Other (OTH) AF: 0.00 AC: 0 AN: 44316

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152242 Hom.: 1 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

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	0.079
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.86
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.11	T
PhyloP100		-0.22
PROVEAN	Benign	-0.81	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.33	T
Vest4		0.20
MVP		0.49
GERP RS		1.3
Varity_R		0.035
Mutation Taster		=94/6	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: rs1846380159; hg19: chr10-135081483;