dbSNP rs5471: HP:c.-91A>C (chr16-72054562-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005143.5(HP):c.-91A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,583,926 control chromosomes in the GnomAD database, including 610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Affects (no stars).

Frequency

Genomes: 𝑓 0.036 ( 324 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 286 hom. )

Consequence

HP
NM_005143.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Affects no assertion criteria provided O:1

Conservation

PhyloP100: 1.84

Publications

19 publications found

Variant links:

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]

HP links:

ENSG00000310525 (HGNC:):

ENSG00000310525 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HP	NM_005143.5 link	c.-91A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000355906.10	NP_005134.1	P00738-1Q6PEJ8
HP	NM_005143.5 link	c.-91A>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000355906.10	NP_005134.1	P00738-1Q6PEJ8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HP	ENST00000355906.10 link	c.-91A>C	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_005143.5	ENSP00000348170.5	P00738-1
HP	ENST00000355906.10 link	c.-91A>C	5_prime_UTR_variant	Exon 1 of 7	1	NM_005143.5	ENSP00000348170.5	P00738-1
ENSG00000310525	ENST00000562153.6 link	n.285-10205T>G	intron_variant	Intron 3 of 5	4		ENSP00000454635.2	H3BN11

Frequencies

GnomAD3 genomes

AF:

0.0359

AC:

5468

AN:

152164

Hom.:

324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0197

GnomAD2 exomes

AF:

0.00791

AC:

1636

AN:

206866

AF XY:

0.00584

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.00413

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00319

GnomAD4 exome

AF:

0.00345

AC:

4934

AN:

1431644

Hom.:

286

Cov.:

AF XY:

0.00298

AC XY:

2112

AN XY:

709696

show subpopulations

African (AFR)

AF:

0.128

AC:

4165

AN:

32652

American (AMR)

AF:

0.00498

AC:

198

AN:

39746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25576

East Asian (EAS)

AF:

0.00

AC:

AN:

38204

South Asian (SAS)

AF:

0.000277

AC:

AN:

83128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51724

Middle Eastern (MID)

AF:

0.00349

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000785

AC:

AN:

1095600

Other (OTH)

AF:

0.00746

AC:

442

AN:

59288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

230

460

689

919

1149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0359

AC:

5471

AN:

152282

Hom.:

324

Cov.:

AF XY:

0.0343

AC XY:

2557

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.126

AC:

5247

AN:

41556

American (AMR)

AF:

0.0104

AC:

159

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68034

Other (OTH)

AF:

0.0194

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

232

464

695

927

1159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0521

Hom.:

101

Bravo

AF:

0.0404

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Anhaptoglobinemia

Other:1

Nov 01, 2003

OMIM

Significance:Affects

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.58

PhyloP100

1.8

PromoterAI

-0.19

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over