chr4-73408586-C-T

Position:

• chr4-73408586-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000477.7(ALB):​c.271-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,178 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 32)
  • Exomes 𝑓: 0.020 (337 hom.)
• Consequence: ALB NM_000477.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006074
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0700

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-73408586-C-T is Benign according to our data. Variant chr4-73408586-C-T is described in ClinVar as [Benign]. Clinvar id is 349617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-73408586-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0134 (2044/152256) while in subpopulation NFE AF= 0.0224 (1522/68004). AF 95% confidence interval is 0.0214. There are 20 homozygotes in gnomad4. There are 899 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALB	NM_000477.7	c.271-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000295897.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALB	ENST00000295897.9	c.271-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000477.7	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2046 AN: 152138 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.0118 AC: 2951 AN: 250228 Hom.: 22 AF XY: 0.0116 AC XY: 1571 AN XY: 135344

Gnomad AFR exome AF: 0.00383

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00714

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0195 AC: 28531 AN: 1460922 Hom.: 337 Cov.: 30 AF XY: 0.0189 AC XY: 13771 AN XY: 726752

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00690

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0134 AC: 2044 AN: 152256 Hom.: 20 Cov.: 32 AF XY: 0.0121 AC XY: 899 AN XY: 74446

Gnomad4 AFR AF: 0.00421

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.0224

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0173 Hom.: 11

Bravo AF: 0.0134

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0221

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Hyperthyroxinemia, familial dysalbuminemic Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.83
CADD	Benign	2.4
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0
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: rs55888080; hg19: chr4-74274303;