chr15-43801560-G-A

Position:

• chr15-43801560-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016400.4(HYPK):​c.261G>A​(p.Leu87=) variant causes a synonymous 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. 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_016400.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.605

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-C15ORF63 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -21 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 id is 714534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.605 with no splicing effect.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYPK	NM_016400.4	c.261G>A	p.Leu87=	synonymous_variant	3/4	ENST00000442995.4
SERF2-C15ORF63	NR_037673.1	n.906G>A		non_coding_transcript_exon_variant	5/6
HYPK	NM_001199885.1	c.229G>A	p.Gly77Arg	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYPK	ENST00000442995.4	c.261G>A	p.Leu87=	synonymous_variant	3/4	1	NM_016400.4	P1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1898 AN: 152176 Hom.: 32 Cov.: 32

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

GnomAD3 exomes AF: 0.00327 AC: 821 AN: 251370 Hom.: 18 AF XY: 0.00238 AC XY: 324 AN XY: 135898

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 SAS exome AF: 0.0000980

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.: 53 Cov.: 31 AF XY: 0.00107 AC XY: 775 AN XY: 727132

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.0126 AC: 1915 AN: 152294 Hom.: 33 Cov.: 32 AF XY: 0.0122 AC XY: 912 AN XY: 74478

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00178 Hom.: 10

Bravo AF: 0.0135

ESP6500AA AF: 0.0457 AC: 201

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	3.6	N
REVEL	Benign	0.076
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.13	T
Vest4		0.15
MutPred		0.19		Gain of MoRF binding (P = 0.0284);
MVP		0.48
ClinPred		0.068	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs77134226; hg19: chr15-44093758;