Genetic Variant HP:p.Gly188Gly (chr16-72060233-T-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005143.5(HP):c.564T>G(p.Gly188Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 152,266 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 23 hom. )

Failed GnomAD Quality Control

Consequence

HP
NM_005143.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.911

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 16-72060233-T-G is Benign according to our data. Variant chr16-72060233-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 782963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.911 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HP	NM_005143.5	MANE Select	c.564T>G	p.Gly188Gly	synonymous	Exon 7 of 7	NP_005134.1	P00738-1
HP	NM_001126102.3		c.387T>G	p.Gly129Gly	synonymous	Exon 5 of 5	NP_001119574.1	P00738-2
HP	NM_001318138.2		c.387T>G	p.Gly129Gly	synonymous	Exon 5 of 5	NP_001305067.1	A0A0C4DGL8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HP	ENST00000355906.10	TSL:1 MANE Select	c.564T>G	p.Gly188Gly	synonymous	Exon 7 of 7	ENSP00000348170.5	P00738-1
HP	ENST00000398131.6	TSL:1	c.387T>G	p.Gly129Gly	synonymous	Exon 5 of 5	ENSP00000381199.2	P00738-2
HP	ENST00000565574.5	TSL:1	c.387T>G	p.Gly129Gly	synonymous	Exon 5 of 5	ENSP00000454966.1	A0A0C4DGL8

Frequencies

GnomAD3 genomes

AF:

0.00327

AC:

497

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00144

AC:

359

AN:

248890

AF XY:

0.00143

show subpopulations

Gnomad AFR exome

AF:

0.00285

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00184

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00156

AC:

2269

AN:

1458452

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1152

AN XY:

725608

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00282

AC:

AN:

33334

American (AMR)

AF:

0.00179

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26128

East Asian (EAS)

AF:

0.00232

AC:

AN:

39630

South Asian (SAS)

AF:

0.00253

AC:

218

AN:

86118

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00147

AC:

1630

AN:

1109132

Other (OTH)

AF:

0.00181

AC:

109

AN:

60282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

155

310

466

621

776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00327

AC:

498

AN:

152266

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

252

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00501

AC:

208

AN:

41550

American (AMR)

AF:

0.00327

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.00174

AC:

AN:

5158

South Asian (SAS)

AF:

0.00311

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00285

AC:

194

AN:

68032

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00243

Hom.:

Bravo

AF:

0.00329

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.3

(source)

DANN

Benign

0.58

PhyloP100

0.91

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over