Variant 6-146666817-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024694.4(ADGB):c.754A>C(p.Ile252Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 1,543,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ADGB
NM_024694.4 missense, splice_region

Scores

Splicing: ADA: 0.001462

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

Variant links:

Genes affected

ADGB (HGNC:21212): (androglobin) Predicted to enable calcium-dependent cysteine-type endopeptidase activity; heme binding activity; and oxygen binding activity. Predicted to be involved in proteolysis. [provided by Alliance of Genome Resources, Apr 2022]

ADGB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13218513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGB	NM_024694.4 linkuse as main transcript	c.754A>C	p.Ile252Leu	missense_variant, splice_region_variant	7/36	ENST00000397944.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGB	ENST00000397944.8 linkuse as main transcript	c.754A>C	p.Ile252Leu	missense_variant, splice_region_variant	7/36	5	NM_024694.4	P4	Q8N7X0-1
ADGB	ENST00000493950.6 linkuse as main transcript	c.613-5403A>C		intron_variant, NMD_transcript_variant		1
ADGB	ENST00000681847.1 linkuse as main transcript	c.754A>C	p.Ile252Leu	missense_variant, splice_region_variant	7/36			A2
ADGB	ENST00000326929.8 linkuse as main transcript	n.795A>C		splice_region_variant, non_coding_transcript_exon_variant	7/18	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000637

AC:

AN:

156966

Hom.:

AF XY:

0.0000121

AC XY:

AN XY:

82742

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000287

AC:

AN:

1391456

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

686284

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000373

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74188

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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

Feb 10, 2023

The c.754A>C (p.I252L) alteration is located in exon 7 (coding exon 7) of the ADGB gene. This alteration results from a A to C substitution at nucleotide position 754, causing the isoleucine (I) at amino acid position 252 to be replaced by a leucine (L). 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

0.15

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.039

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.57

M_CAP

Benign

0.029

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.48

REVEL

Benign

0.28

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.051

Vest4

0.34

MutPred

0.50

Gain of loop (P = 0.069);

MVP

0.16

ClinPred

0.11

GERP RS

3.0

Varity_R

0.049

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.020

SpliceAI score (max)

0.030

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