16-72056546-GC-GCC

Variant names:

• chr16-72056546-G-GC
• rs778198124
• NM_005143.5:c.111dupC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005143.5(HP):​c.111dupC​(p.Glu38ArgfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,369,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HP NM_005143.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.357
• Publications: 0 publications found

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]

ENSG00000310525 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005143.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HP	NM_005143.5	MANE Select	c.111dupC	p.Glu38ArgfsTer16	frameshift	Exon 3 of 7	NP_005134.1
	HP	NM_001126102.3		c.111dupC	p.Glu38ArgfsTer16	frameshift	Exon 3 of 5	NP_001119574.1
	HP	NM_001318138.2		c.111dupC	p.Glu38ArgfsTer16	frameshift	Exon 3 of 5	NP_001305067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HP	ENST00000355906.10	TSL:1 MANE Select	c.111dupC	p.Glu38ArgfsTer16	frameshift	Exon 3 of 7	ENSP00000348170.5
	HP	ENST00000398131.6	TSL:1	c.111dupC	p.Glu38ArgfsTer16	frameshift	Exon 3 of 5	ENSP00000381199.2
	HP	ENST00000565574.5	TSL:1	c.111dupC	p.Glu38ArgfsTer16	frameshift	Exon 3 of 5	ENSP00000454966.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 136848 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000126 AC: 2 AN: 158426 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000438 AC: 6 AN: 1369508 Hom.: 0 Cov.: 23 AF XY: 0.00000443 AC XY: 3 AN XY: 676942

African (AFR) AF: 0.00 AC: 0 AN: 30998

American (AMR) AF: 0.00 AC: 0 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24948

East Asian (EAS) AF: 0.000141 AC: 5 AN: 35546

South Asian (SAS) AF: 0.00 AC: 0 AN: 78674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4326

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1053076

Other (OTH) AF: 0.00 AC: 0 AN: 56882

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 136956 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 65862

African (AFR) AF: 0.00 AC: 0 AN: 35770

American (AMR) AF: 0.00 AC: 0 AN: 13298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3334

East Asian (EAS) AF: 0.00 AC: 0 AN: 4486

South Asian (SAS) AF: 0.00 AC: 0 AN: 3708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64182

Other (OTH) AF: 0.00 AC: 0 AN: 1794

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Anhaptoglobinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=23/177	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs778198124; hg19: chr16-72090445; COSMIC: COSV100577468;