rs76285851

chr4-73405117-C-Achr4-73405117-C-Gchr4-73405117-C-Nchr4-73405117-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000477.7(ALB):c.81C>A(p.His27Gln) variant causes a missense, splice region 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. 14/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H27?) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALB NM_000477.7 missense, splice_region
• Scores: Splicing: ADA: 0.00008424
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0750

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3274687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALB	NM_000477.7	c.81C>A	p.His27Gln	missense_variant, splice_region_variant	2/15	ENST00000295897.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALB	ENST00000295897.9	c.81C>A	p.His27Gln	missense_variant, splice_region_variant	2/15	1	NM_000477.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 23, 2023

This variant is also known as Nagasaki-3 or His3Gln. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects ALB function (PMID: 3478700). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This variant has not been reported in the literature in individuals affected with ALB-related conditions. This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 27 of the ALB protein (p.His27Gln). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.076	T;D;.;.;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.53	T;T;T;T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.9	D;D;.;.;N;D;N
REVEL	Benign	0.23
Sift	Benign	0.032	D;T;.;.;T;T;D
Sift4G	Uncertain	0.018	D;D;D;D;T;D;D
Polyphen		0.023, 0.0090, 0.94	.;B;.;.;B;.;P
Vest4		0.22, 0.28, 0.28, 0.21, 0.22, 0.18
MutPred		0.25		.;Loss of stability (P = 0.0514);Loss of stability (P = 0.0514);Loss of stability (P = 0.0514);Loss of stability (P = 0.0514);Loss of stability (P = 0.0514);Loss of stability (P = 0.0514);
MVP		0.86
MPC		0.21
ClinPred		0.78	D
GERP RS		0.48
Varity_R		0.36
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000084
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76285851; hg19: chr4-74270834;