16-72060449-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_005143.5(HP):c.780G>A(p.Glu260=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,614,158 control chromosomes in the GnomAD database, including 1,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (131 hom., cov: 31)
  • Exomes 𝑓: 0.046 (1823 hom.)
• Consequence: HP NM_005143.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.620

Genes affected

HP (HGNC:5141): (haptoglobin) This gene encodes a preproprotein, which is processed to yield both alpha and beta chains, which subsequently combine as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin, while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin. Mutations in this gene and/or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy, the incidence of coronary artery disease in type 1 diabetes, Crohn's disease, inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease, and a reduced incidence of Plasmodium falciparum malaria. The protein encoded also exhibits antimicrobial activity against bacteria. A similar duplicated gene is located next to this gene on chromosome 16. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

TXNL4B (HGNC:26041): (thioredoxin like 4B) Predicted to be involved in mRNA splicing, via spliceosome. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-72060449-G-A is Benign according to our data. Variant chr16-72060449-G-A is described in ClinVar as [Benign]. Clinvar id is 3060365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.62 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HP	NM_005143.5	c.780G>A	p.Glu260=	synonymous_variant	7/7	ENST00000355906.10
HP	NM_001126102.3	c.603G>A	p.Glu201=	synonymous_variant	5/5
HP	NM_001318138.2	c.603G>A	p.Glu201=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HP	ENST00000355906.10	c.780G>A	p.Glu260=	synonymous_variant	7/7	1	NM_005143.5	A2

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4789 AN: 152170 Hom.: 131 Cov.: 31

Gnomad AFR AF: 0.00823

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0737

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0307 AC: 7665 AN: 249438 Hom.: 179 AF XY: 0.0312 AC XY: 4224 AN XY: 135326

Gnomad AFR exome AF: 0.00827

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.00944

Gnomad FIN exome AF: 0.0736

Gnomad NFE exome AF: 0.0444

Gnomad OTH exome AF: 0.0276

GnomAD4 exome AF: 0.0463 AC: 67668 AN: 1461870 Hom.: 1823 Cov.: 31 AF XY: 0.0453 AC XY: 32923 AN XY: 727236

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00968

Gnomad4 FIN exome AF: 0.0740

Gnomad4 NFE exome AF: 0.0537

Gnomad4 OTH exome AF: 0.0368

GnomAD4 genome AF: 0.0314 AC: 4789 AN: 152288 Hom.: 131 Cov.: 31 AF XY: 0.0322 AC XY: 2396 AN XY: 74452

Gnomad4 AFR AF: 0.00820

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.0737

Gnomad4 NFE AF: 0.0462

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0377 Hom.: 142

Bravo AF: 0.0276

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0404

EpiControl AF: 0.0407

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	4.9
Dann	Benign	0.72

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: rs5475; hg19: chr16-72094348;