rs4336470

Variant names:

• chr6-104732910-C-T
• rs4336470
• NM_020771.4:c.2514-2494G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020771.4(HACE1):​c.2514-2494G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 151,982 control chromosomes in the GnomAD database, including 17,279 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (17279 hom., cov: 33)
• Consequence: HACE1 NM_020771.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.568
• Publications: 28 publications found

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]

HACE1 Gene-Disease associations (from GenCC):

• spastic paraplegia-severe developmental delay-epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020771.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACE1	NM_020771.4	MANE Select	c.2514-2494G>A		intron	N/A	NP_065822.2	Q8IYU2-1
	HACE1	NM_001321083.2		c.2412-2494G>A		intron	N/A	NP_001308012.1
	HACE1	NM_001321080.2		c.2382-2494G>A		intron	N/A	NP_001308009.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACE1	ENST00000262903.9	TSL:1 MANE Select	c.2514-2494G>A		intron	N/A	ENSP00000262903.4	Q8IYU2-1
	HACE1	ENST00000369127.8	TSL:1	n.3535-2494G>A		intron	N/A
	HACE1	ENST00000416605.6	TSL:1	n.*2176-2494G>A		intron	N/A	ENSP00000392425.2	E3W983

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67584 AN: 151864 Hom.: 17241 Cov.: 33

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.406

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.445 AC: 67675 AN: 151982 Hom.: 17279 Cov.: 33 AF XY: 0.439 AC XY: 32580 AN XY: 74264

African (AFR) AF: 0.716 AC: 29714 AN: 41478

American (AMR) AF: 0.387 AC: 5911 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1372 AN: 5162

South Asian (SAS) AF: 0.312 AC: 1505 AN: 4818

European-Finnish (FIN) AF: 0.309 AC: 3258 AN: 10538

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23584 AN: 67922

Other (OTH) AF: 0.402 AC: 849 AN: 2112

Alfa AF: 0.381 Hom.: 30528

Bravo AF: 0.466

Asia WGS AF: 0.262 AC: 912 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.94
DANN	Benign	0.52
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4336470; hg19: chr6-105180785; COSMIC: COSV53500347; COSMIC: COSV53500347;