4-73419522-C-T

Variant names:

• chr4-73419522-C-T
• rs962004
• NM_000477.7:c.1668C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000477.7(ALB):​c.1668C>T​(p.Leu556Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,611,588 control chromosomes in the GnomAD database, including 252,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20147 hom., cov: 28)
  • Exomes 𝑓: 0.56 (232673 hom.)
• Consequence: ALB NM_000477.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 4-73419522-C-T is Benign according to our data. Variant chr4-73419522-C-T is described in ClinVar as [Benign]. Clinvar id is 349639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-73419522-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALB	NM_000477.7	c.1668C>T	p.Leu556Leu	synonymous_variant	Exon 13 of 15	ENST00000295897.9	NP_000468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALB	ENST00000295897.9	c.1668C>T	p.Leu556Leu	synonymous_variant	Exon 13 of 15	1	NM_000477.7	ENSP00000295897.4

Frequencies

GnomAD3 genomes AF: 0.510 AC: 76947 AN: 150784 Hom.: 20154 Cov.: 28

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.480

GnomAD3 exomes AF: 0.527 AC: 132083 AN: 250552 Hom.: 35632 AF XY: 0.534 AC XY: 72290 AN XY: 135420

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.456

Gnomad EAS exome AF: 0.571

Gnomad SAS exome AF: 0.506

Gnomad FIN exome AF: 0.553

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.562 AC: 820724 AN: 1460692 Hom.: 232673 Cov.: 46 AF XY: 0.562 AC XY: 408261 AN XY: 726654

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.414

Gnomad4 ASJ exome AF: 0.455

Gnomad4 EAS exome AF: 0.531

Gnomad4 SAS exome AF: 0.512

Gnomad4 FIN exome AF: 0.559

Gnomad4 NFE exome AF: 0.582

Gnomad4 OTH exome AF: 0.535

GnomAD4 genome AF: 0.510 AC: 76953 AN: 150896 Hom.: 20147 Cov.: 28 AF XY: 0.507 AC XY: 37352 AN XY: 73618

Gnomad4 AFR AF: 0.409

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.548

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.474

Alfa AF: 0.563 Hom.: 33740

Bravo AF: 0.496

Asia WGS AF: 0.467 AC: 1625 AN: 3478

EpiCase AF: 0.562

EpiControl AF: 0.559

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperthyroxinemia, familial dysalbuminemic Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs962004; hg19: chr4-74285239; COSMIC: COSV55738606; COSMIC: COSV55738606;