rs5470

Positions:

• chr16-72054522-C-G
• chr16-72054522-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005143.5(HP):​c.-131C>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 0.00708 in 1,560,710 control chromosomes in the GnomAD database, including 612 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 0.038 (318 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (294 hom.)
• Consequence: HP NM_005143.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.757

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HP	NM_005143.5	c.-131C>G		5_prime_UTR_variant	1/7	ENST00000355906.10	NP_005134.1
HP	NM_001126102.3	c.-131C>G		5_prime_UTR_variant	1/5		NP_001119574.1
HP	NM_001318138.2	c.-131C>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.-131C>G		5_prime_UTR_variant	1/7	1	NM_005143.5	ENSP00000348170	A2
TXNL4B	ENST00000562153.5	c.285-10165G>C		intron_variant		4		ENSP00000454635

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 5731 AN: 152046 Hom.: 317 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0277

GnomAD4 exome AF: 0.00376 AC: 5302 AN: 1408546 Hom.: 294 AF XY: 0.00320 AC XY: 2229 AN XY: 696426

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.00764

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000173

Gnomad4 FIN exome AF: 0.0000594

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.0377 AC: 5744 AN: 152164 Hom.: 318 Cov.: 33 AF XY: 0.0369 AC XY: 2743 AN XY: 74378

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.000883 Hom.: 2

Bravo AF: 0.0428

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.80

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs5470; hg19: chr16-72088421;