4-73404398-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000477.7(ALB):c.71G>T(p.Arg24Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,459,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as other (no stars). 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. R24P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ALB NM_000477.7 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 5.86

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-73404398-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 18186.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.71G>T	p.Arg24Leu	missense_variant	1/15	ENST00000295897.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALB	ENST00000295897.9	c.71G>T	p.Arg24Leu	missense_variant	1/15	1	NM_000477.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1459892 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726398

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

PROALBUMIN JAFFNA Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.071	T;D;.;.;.;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;T;T;T;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;D;.;.;N;D;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D;D;.;.;T;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0, 0.33, 0.0070	.;D;.;.;B;.;B
Vest4		0.84, 0.77, 0.79, 0.81, 0.81, 0.82
MutPred		0.52		.;Loss of disorder (P = 0.0154);Loss of disorder (P = 0.0154);Loss of disorder (P = 0.0154);Loss of disorder (P = 0.0154);Loss of disorder (P = 0.0154);Loss of disorder (P = 0.0154);
MVP		0.94
MPC		0.67
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.42
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs74821926; hg19: chr4-74270115;