Genetic Variant HYPK:p.Leu87Leu (chr15-43801560-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001199885.1(HYPK):c.229G>A(p.Gly77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,908 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 53 hom. )

Consequence

HYPK
NM_001199885.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.605

Publications

6 publications found

Variant links:

Genes affected

HYPK (HGNC:18418): (huntingtin interacting protein K) Enables protein N-terminus binding activity. Involved in negative regulation of apoptotic process and protein stabilization. Located in cytoplasm; microtubule cytoskeleton; and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

HYPK links:

SERF2 (HGNC:10757): (small EDRK-rich factor 2) Involved in protein destabilization. Predicted to be located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SERF2 links:

SERF2-C15ORF63 (HGNC:):

SERF2-C15ORF63 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017516911).

BP6

Variant 15-43801560-G-A is Benign according to our data. Variant chr15-43801560-G-A is described in ClinVar as Benign. ClinVar VariationId is 714534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1915/152294) while in subpopulation AFR AF = 0.0437 (1818/41564). AF 95% confidence interval is 0.0421. There are 33 homozygotes in GnomAd4. There are 912 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199885.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HYPK	NM_016400.4	MANE Select	c.261G>A	p.Leu87Leu	synonymous	Exon 3 of 4	NP_057484.4
HYPK	NM_001199885.1		c.229G>A	p.Gly77Arg	missense	Exon 2 of 3	NP_001186814.1	Q9NX55
SERF2-C15ORF63	NR_037673.1		n.906G>A		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HYPK	ENST00000442995.4	TSL:1 MANE Select	c.261G>A	p.Leu87Leu	synonymous	Exon 3 of 4	ENSP00000401155.3	Q9NX55-2
HYPK	ENST00000458412.2	TSL:2	c.205G>A	p.Gly69Arg	missense	Exon 2 of 2	ENSP00000394060.2	J3QT56
HYPK	ENST00000406925.7	TSL:2	c.261G>A	p.Leu87Leu	synonymous	Exon 4 of 5	ENSP00000384474.2	Q9NX55-2

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1898

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00327

AC:

821

AN:

251370

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.0457

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00123

AC:

1803

AN:

1461614

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

775

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0441

AC:

1476

AN:

33472

American (AMR)

AF:

0.00210

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000186

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111774

Other (OTH)

AF:

0.00323

AC:

195

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0126

AC:

1915

AN:

152294

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

912

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0437

AC:

1818

AN:

41564

American (AMR)

AF:

0.00510

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

178

267

356

445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00381

Hom.:

Bravo

AF:

0.0135

ESP6500AA

AF:

0.0457

AC:

201

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0056

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

PhyloP100

0.60

PROVEAN

Benign

3.6

REVEL

Benign

0.076

Sift

Pathogenic

0.0

Sift4G

Benign

0.13

Vest4

0.15

MutPred

0.19

Gain of MoRF binding (P = 0.0284)

MVP

0.48

ClinPred

0.068

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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