Variant 4-73408595-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000477.7(ALB):c.272A>G(p.His91Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/23 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: 0.0000048 ( 0 hom. )

Consequence

ALB
NM_000477.7 missense, splice_region

Scores

Splicing: ADA: 0.0001433

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Variant links:

Genes affected

ALB (HGNC:399): (albumin) This gene encodes the most abundant protein in human blood. This protein functions in the regulation of blood plasma colloid osmotic pressure and acts as a carrier protein for a wide range of endogenous molecules including hormones, fatty acids, and metabolites, as well as exogenous drugs. Additionally, this protein exhibits an esterase-like activity with broad substrate specificity. The encoded preproprotein is proteolytically processed to generate the mature protein. A peptide derived from this protein, EPI-X4, is an endogenous inhibitor of the CXCR4 chemokine receptor. [provided by RefSeq, Jul 2016]

ALB links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity ALBU_HUMAN

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALB	NM_000477.7 linkuse as main transcript	c.272A>G	p.His91Arg	missense_variant, splice_region_variant	4/15	ENST00000295897.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALB	ENST00000295897.9 linkuse as main transcript	c.272A>G	p.His91Arg	missense_variant, splice_region_variant	4/15	1	NM_000477.7	P1	P02768-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250882

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135650

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461522

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727066

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 08, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1416088). This variant has not been reported in the literature in individuals affected with ALB-related conditions. This variant is present in population databases (rs773096498, gnomAD 0.003%). This sequence change replaces histidine with arginine at codon 91 of the ALB protein (p.His91Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Benign

0.80

DEOGEN2

Benign

0.017

T;T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.87

D;T;T;T;T

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Benign

-0.30

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

D;D;.;.;D

REVEL

Uncertain

0.34

Sift

Benign

0.35

T;T;.;.;T

Sift4G

Benign

0.31

T;T;T;T;T

Polyphen

0.60

.;P;.;.;.

Vest4

0.46, 0.46, 0.42, 0.45

MutPred

0.43

.;Gain of disorder (P = 0.1191);Gain of disorder (P = 0.1191);Gain of disorder (P = 0.1191);Gain of disorder (P = 0.1191);

MVP

0.81

MPC

0.62

ClinPred

0.79

GERP RS

-1.7

Varity_R

0.48

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.014

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