6-104775989-G-A

Variant names:

• chr6-104775989-G-A
• rs733724
• NM_020771.4:c.1864+752C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_020771.4(HACE1):​c.1864+752C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 152,228 control chromosomes in the GnomAD database, including 359 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 0.061 (359 hom., cov: 33)
• Consequence: HACE1 NM_020771.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155
• Publications: 9 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0838 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACE1	NM_020771.4	MANE Select	c.1864+752C>T		intron	N/A	NP_065822.2
	HACE1	NM_001321083.2		c.1762+752C>T		intron	N/A	NP_001308012.1
	HACE1	NM_001321080.2		c.1732+752C>T		intron	N/A	NP_001308009.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACE1	ENST00000262903.9	TSL:1 MANE Select	c.1864+752C>T		intron	N/A	ENSP00000262903.4
	HACE1	ENST00000369127.8	TSL:1	n.2885+752C>T		intron	N/A
	HACE1	ENST00000416605.6	TSL:1	n.*1526+752C>T		intron	N/A	ENSP00000392425.2

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9292 AN: 152110 Hom.: 357 Cov.: 33

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0656

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0856

Gnomad OTH AF: 0.0827

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

GnomAD4 genome AF: 0.0610 AC: 9292 AN: 152228 Hom.: 359 Cov.: 33 AF XY: 0.0582 AC XY: 4335 AN XY: 74438

African (AFR) AF: 0.0336 AC: 1396 AN: 41540

American (AMR) AF: 0.0655 AC: 1002 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 261 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0391 AC: 189 AN: 4828

European-Finnish (FIN) AF: 0.0303 AC: 321 AN: 10596

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0856 AC: 5821 AN: 68000

Other (OTH) AF: 0.0818 AC: 173 AN: 2114

Alfa AF: 0.0708 Hom.: 405

Bravo AF: 0.0637

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.4
DANN	Benign	0.92
PhyloP100		-0.15
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: rs733724; hg19: chr6-105223864;