Genetic Variant NM_001109.5:c.1969T>A (chr10-133268842-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001109.5(ADAM8):c.1969T>A(p.Phe657Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 36)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAM8
NM_001109.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.831

Publications

30 publications found

Variant links:

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]

ADAM8 links:

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ACMG classification

Classification was made for transcript

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=0.07180244).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM8	NM_001109.5	MANE Select	c.1969T>A	p.Phe657Ile	missense	Exon 19 of 23	NP_001100.3	P78325-1
ADAM8	NM_001164490.2		c.1774T>A	p.Phe592Ile	missense	Exon 17 of 20	NP_001157962.1	P78325-2
ADAM8	NM_001164489.2		c.1948+603T>A		intron	N/A	NP_001157961.1	P78325-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.1969T>A	p.Phe657Ile	missense	Exon 19 of 23	ENSP00000453302.1	P78325-1
ADAM8	ENST00000415217.7	TSL:1	c.1948+603T>A		intron	N/A	ENSP00000453855.1	P78325-3
ADAM8	ENST00000897047.1		c.1963T>A	p.Phe655Ile	missense	Exon 19 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1456188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724660

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111744

Other (OTH)

AF:

0.00

AC:

AN:

60320

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.076

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.037

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.22

M_CAP

Benign

0.0047

MetaRNN

Benign

0.072

MutationAssessor

Benign

0.69

PhyloP100

-0.83

PrimateAI

Benign

0.38

PROVEAN

Benign

0.17

Sift

Benign

0.40

Sift4G

Benign

0.40

Vest4

0.11

MVP

0.44

MPC

0.17

GERP RS

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.019

gMVP

0.29

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over