6-104744232-TAAC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020771.4(HACE1):c.2443-5_2443-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,575,176 control chromosomes in the GnomAD database, including 24,603 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4917 hom., cov: 26)
  • Exomes 𝑓: 0.15 (19686 hom.)
• Consequence: HACE1 NM_020771.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.25

Genes affected

HACE1 (HGNC:21033): (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1) This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm's tumor. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 6-104744232-TAAC-T is Benign according to our data. Variant chr6-104744232-TAAC-T is described in ClinVar as [Benign]. Clinvar id is 1599999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HACE1	NM_020771.4	c.2443-5_2443-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262903.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HACE1	ENST00000262903.9	c.2443-5_2443-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020771.4	P1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34021 AN: 151752 Hom.: 4900 Cov.: 26

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.164 AC: 41071 AN: 250952 Hom.: 4173 AF XY: 0.160 AC XY: 21687 AN XY: 135652

Gnomad AFR exome AF: 0.421

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.00495

Gnomad SAS exome AF: 0.159

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.155 AC: 220054 AN: 1423308 Hom.: 19686 AF XY: 0.155 AC XY: 110098 AN XY: 710576

Gnomad4 AFR exome AF: 0.418

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.00563

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.224 AC: 34077 AN: 151868 Hom.: 4917 Cov.: 26 AF XY: 0.221 AC XY: 16372 AN XY: 74232

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.00676

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.200

Alfa AF: 0.190 Hom.: 617

Bravo AF: 0.240

Asia WGS AF: 0.0930 AC: 321 AN: 3470

EpiCase AF: 0.164

EpiControl AF: 0.166

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Spastic paraplegia-severe developmental delay-epilepsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72218235; hg19: chr6-105192107;