rs5472

Positions:

• chr16-72054568-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005143.5(HP):​c.-85A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 146,828 control chromosomes in the GnomAD database, including 4,530 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (4530 hom., cov: 32)
  • Exomes 𝑓: 0.30 (6406 hom.)
  • Failed GnomAD Quality Control
• Consequence: HP NM_005143.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.249

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HP	NM_005143.5	c.-85A>G		5_prime_UTR_variant	1/7	ENST00000355906.10	NP_005134.1
HP	NM_001126102.3	c.-85A>G		5_prime_UTR_variant	1/5		NP_001119574.1
HP	NM_001318138.2	c.-85A>G		5_prime_UTR_variant	1/5		NP_001305067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HP	ENST00000355906.10	c.-85A>G		5_prime_UTR_variant	1/7	1	NM_005143.5	ENSP00000348170	A2
TXNL4B	ENST00000562153.5	c.285-10211T>C		intron_variant		4		ENSP00000454635
HP	ENST00000398131.6			upstream_gene_variant		1		ENSP00000381199	P3
HP	ENST00000570083.5			upstream_gene_variant		1		ENSP00000457629	P3

Frequencies

GnomAD3 genomes AF: 0.328 AC: 48192 AN: 146714 Hom.: 4528 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.448

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.339

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.299 AC: 424216 AN: 1420780 Hom.: 6406 Cov.: 35 AF XY: 0.301 AC XY: 212131 AN XY: 704288

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.240

Gnomad4 ASJ exome AF: 0.341

Gnomad4 EAS exome AF: 0.280

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.299

Gnomad4 NFE exome AF: 0.294

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.328 AC: 48217 AN: 146828 Hom.: 4530 Cov.: 32 AF XY: 0.326 AC XY: 23410 AN XY: 71838

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.352

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.400

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.335

Alfa AF: 0.332 Hom.: 819

Asia WGS AF: 0.327 AC: 1138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.66

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5472; hg19: chr16-72088467; COSMIC: COSV63325898;