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GeneBe

15-43801711-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016400.4(HYPK):c.271A>G(p.Met91Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

HYPK
NM_016400.4 missense, splice_region

Scores

1
6
10
Splicing: ADA: 0.9183
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.06
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HYPKNM_016400.4 linkuse as main transcriptc.271A>G p.Met91Val missense_variant, splice_region_variant 4/4 ENST00000442995.4
SERF2-C15ORF63NR_037673.1 linkuse as main transcriptn.916A>G splice_region_variant, non_coding_transcript_exon_variant 6/6
HYPKNM_001199885.1 linkuse as main transcriptc.239A>G p.Asn80Ser missense_variant, splice_region_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HYPKENST00000442995.4 linkuse as main transcriptc.271A>G p.Met91Val missense_variant, splice_region_variant 4/41 NM_016400.4 P1Q9NX55-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251486
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000479
AC:
70
AN:
1461834
Hom.:
0
Cov.:
31
AF XY:
0.0000481
AC XY:
35
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000603
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000555
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 16, 2022The c.295A>G (p.M99V) alteration is located in exon 4 (coding exon 4) of the HYPK gene. This alteration results from a A to G substitution at nucleotide position 295, causing the methionine (M) at amino acid position 99 to be replaced by a valine (V). 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
0.11
BayesDel_addAF
Uncertain
0.077
D
BayesDel_noAF
Uncertain
0.0
Cadd
Benign
21
Dann
Benign
0.93
DEOGEN2
Benign
0.0081
T;T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Benign
0.073
D
MetaRNN
Uncertain
0.65
D;D
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.14
N;N
REVEL
Benign
0.20
Sift
Benign
0.78
T;T
Sift4G
Benign
0.81
T;T
Polyphen
0.0030
B;B
Vest4
0.83
MVP
0.74
MPC
0.70
ClinPred
0.72
D
GERP RS
5.4
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.38
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.92
dbscSNV1_RF
Pathogenic
0.77
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201828726; hg19: chr15-44093909; API