Variant 6-146672465-A-G 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.1085A>G(p.Lys362Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000724 in 1,381,056 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: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ADGB
NM_024694.4 missense, splice_region

Scores

Splicing: ADA: 0.05145

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

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:

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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=0.1523571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGB	NM_024694.4 linkuse as main transcript	c.1085A>G	p.Lys362Arg	missense_variant, splice_region_variant	8/36	ENST00000397944.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGB	ENST00000397944.8 linkuse as main transcript	c.1085A>G	p.Lys362Arg	missense_variant, splice_region_variant	8/36	5	NM_024694.4	P4	Q8N7X0-1
ADGB	ENST00000493950.6 linkuse as main transcript	c.*195A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/32	1
ADGB	ENST00000681847.1 linkuse as main transcript	c.1085A>G	p.Lys362Arg	missense_variant, splice_region_variant	8/36			A2
ADGB	ENST00000326929.8 linkuse as main transcript	n.1126A>G		splice_region_variant, non_coding_transcript_exon_variant	8/18	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000709

AC:

AN:

141138

Hom.:

AF XY:

0.00

AC XY:

AN XY:

74520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000996

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.24e-7

AC:

AN:

1381056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

680170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000281

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

Cov.:

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

Apr 17, 2023

The c.1085A>G (p.K362R) alteration is located in exon 8 (coding exon 8) of the ADGB gene. This alteration results from a A to G substitution at nucleotide position 1085, causing the lysine (K) at amino acid position 362 to be replaced by an arginine (R). 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

0.086

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0074

Eigen

Benign

0.049

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.53

M_CAP

Benign

0.018

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.77

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.72

REVEL

Benign

0.033

Sift

Benign

0.15

Sift4G

Benign

0.29

Polyphen

0.40

Vest4

0.20

MutPred

0.20

Loss of methylation at K362 (P = 0.0151);

MVP

0.055

ClinPred

0.40

GERP RS

5.2

Varity_R

0.088

gMVP

0.077

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.051

dbscSNV1_RF

Benign

0.31

SpliceAI score (max)

0.020

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