rs75353611

chr4-73404401-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000477.7(ALB):c.74A>T(p.Asp25Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ALB NM_000477.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-73404401-A-T is Pathogenic according to our data. Variant chr4-73404401-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 18187.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALB	NM_000477.7	c.74A>T	p.Asp25Val	missense_variant	1/15	ENST00000295897.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALB	ENST00000295897.9	c.74A>T	p.Asp25Val	missense_variant	1/15	1	NM_000477.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459636 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726290

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alloalbuminemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;D;.;.;.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;T;T;T;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.9	D;D;.;.;N;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D;.;.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.99, 0.16, 0.99	.;D;.;.;B;.;D
Vest4		0.35, 0.42, 0.47, 0.41, 0.40, 0.43
MutPred		0.45		.;Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);
MVP		0.82
MPC		0.35
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.49
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs75353611; hg19: chr4-74270118;