16-72056201-C-A

Position:

• chr16-72056201-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005143.5(HP):​c.46C>A​(p.Leu16Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40280017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HP	NM_005143.5	c.46C>A	p.Leu16Ile	missense_variant	2/7	ENST00000355906.10	NP_005134.1
HP	NM_001126102.3	c.46C>A	p.Leu16Ile	missense_variant	2/5		NP_001119574.1
HP	NM_001318138.2	c.46C>A	p.Leu16Ile	missense_variant	2/5		NP_001305067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HP	ENST00000355906.10	c.46C>A	p.Leu16Ile	missense_variant	2/7	1	NM_005143.5	ENSP00000348170.5
TXNL4B	ENST00000562153.5	c.285-11844G>T		intron_variant		4		ENSP00000454635.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249448 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461792 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

The c.46C>A (p.L16I) alteration is located in exon 2 (coding exon 2) of the HP gene. This alteration results from a C to A substitution at nucleotide position 46, causing the leucine (L) at amino acid position 16 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.34	.;T;.;T;.;.;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.76	.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.1	M;M;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.25	N;N;N;.;N;N;N;N;.
REVEL	Uncertain	0.41
Sift	Benign	0.032	D;D;D;.;D;T;D;D;.
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.49
MutPred		0.39		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.80
MPC		0.34
ClinPred		0.49	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.11

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: rs753062127; hg19: chr16-72090100;