Genetic Variant ALB:p.His27Gln (chr4-73405117-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

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. 15/26 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H27Y) 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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

congenital analbuminemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
hyperthyroxinemia, familial dysalbuminemic
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ALB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000477.7

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3274687).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000477.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALB	NM_000477.7	MANE Select	c.81C>A	p.His27Gln	missense splice_region	Exon 2 of 15	NP_000468.1	P02768-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALB	ENST00000295897.9	TSL:1 MANE Select	c.81C>A	p.His27Gln	missense splice_region	Exon 2 of 15	ENSP00000295897.4	P02768-1
ALB	ENST00000415165.6	TSL:1	c.81C>A	p.His27Gln	missense splice_region	Exon 2 of 11	ENSP00000401820.2	C9JKR2
ALB	ENST00000876051.1		c.81C>A	p.His27Gln	missense splice_region	Exon 2 of 15	ENSP00000546110.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.076

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.095

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.53

M_CAP

Benign

0.043

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.2

PhyloP100

0.075

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.23

Sift

Benign

0.032

Sift4G

Uncertain

0.018

Polyphen

0.023

Vest4

0.22

MutPred

0.25

Loss of stability (P = 0.0514)

MVP

0.86

MPC

0.21

ClinPred

0.78

GERP RS

0.48

Varity_R

0.36

gMVP

0.12

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over