Variant 14-70457642-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003813.4(ADAM21):c.143T>A(p.Val48Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAM21
NM_003813.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.186

Variant links:

Genes affected

ADAM21 (HGNC:200): (ADAM metallopeptidase domain 21) 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 expression of this gene expression is testis-specific. [provided by RefSeq, May 2011]

ADAM21 links:

(HGNC:):

links:

ADAM20P1 (HGNC:20102): (ADAM metallopeptidase domain 20 pseudogene 1)

ADAM20P1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM21	NM_003813.4 linkuse as main transcript	c.143T>A	p.Val48Glu	missense_variant	2/2	ENST00000603540.2	NP_003804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ADAM21	ENST00000603540.2 linkuse as main transcript	c.143T>A	p.Val48Glu	missense_variant	2/2	3	NM_003813.4	ENSP00000474385	P1
	ENST00000556646.1 linkuse as main transcript	n.184-4133A>T		intron_variant, non_coding_transcript_variant		4
ADAM20P1	ENST00000649019.1 linkuse as main transcript	n.507-2214A>T		intron_variant, non_coding_transcript_variant
ADAM21	ENST00000679631.1 linkuse as main transcript	c.143T>A	p.Val48Glu	missense_variant	2/2			ENSP00000506213	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461434

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.143T>A (p.V48E) alteration is located in exon 2 (coding exon 1) of the ADAM21 gene. This alteration results from a T to A substitution at nucleotide position 143, causing the valine (V) at amino acid position 48 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.41

M_CAP

Benign

0.0069

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.46

MutPred

0.82

Gain of disorder (P = 0.0086);

MVP

0.41

MPC

1.6

ClinPred

0.83

GERP RS

2.5

Varity_R

0.66

gMVP

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over