4-73419522-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L556L) has been classified as Uncertain significance.

• 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
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.047).
• BP6: Variant 4-73419522-C-T is Benign according to our data. Variant chr4-73419522-C-T is described in ClinVar as Benign. ClinVar VariationId is 349639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1668C>T	p.Leu556Leu	synonymous	Exon 13 of 15	NP_000468.1	P02768-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALB	ENST00000295897.9	TSL:1 MANE Select	c.1668C>T	p.Leu556Leu	synonymous	Exon 13 of 15	ENSP00000295897.4	P02768-1
	ALB	ENST00000415165.6	TSL:1	c.1092C>T	p.Leu364Leu	synonymous	Exon 9 of 11	ENSP00000401820.2	C9JKR2
	ALB	ENST00000876051.1		c.1731C>T	p.Leu577Leu	synonymous	Exon 13 of 15	ENSP00000546110.1

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

GnomAD2 exomes AF: 0.527 AC: 132083 AN: 250552 AF XY: 0.534

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 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

African (AFR) AF: 0.398 AC: 13333 AN: 33466

American (AMR) AF: 0.414 AC: 18505 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11892 AN: 26118

East Asian (EAS) AF: 0.531 AC: 21071 AN: 39676

South Asian (SAS) AF: 0.512 AC: 44185 AN: 86218

European-Finnish (FIN) AF: 0.559 AC: 29816 AN: 53340

Middle Eastern (MID) AF: 0.464 AC: 2672 AN: 5754

European-Non Finnish (NFE) AF: 0.582 AC: 646938 AN: 1111126

Other (OTH) AF: 0.535 AC: 32312 AN: 60348

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

African (AFR) AF: 0.409 AC: 16782 AN: 41054

American (AMR) AF: 0.438 AC: 6629 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1539 AN: 3462

East Asian (EAS) AF: 0.554 AC: 2846 AN: 5134

South Asian (SAS) AF: 0.512 AC: 2438 AN: 4762

European-Finnish (FIN) AF: 0.548 AC: 5646 AN: 10308

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39418 AN: 67740

Other (OTH) AF: 0.474 AC: 993 AN: 2094

Alfa AF: 0.560 Hom.: 71703

Bravo AF: 0.496

Asia WGS AF: 0.467 AC: 1625 AN: 3478

EpiCase AF: 0.562

EpiControl AF: 0.559

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyperthyroxinemia, familial dysalbuminemic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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