6-104734964-T-C

Variant names:

• chr6-104734964-T-C
• rs7741733
• NM_020771.4:c.2514-4548A>G

Variant summary

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

The NM_020771.4(HACE1):​c.2514-4548A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 151,860 control chromosomes in the GnomAD database, including 25,193 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 0.56 (25193 hom., cov: 32)
• Consequence: HACE1 NM_020771.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.177
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HACE1	NM_020771.4	c.2514-4548A>G		intron_variant	Intron 22 of 23	ENST00000262903.9	NP_065822.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HACE1	ENST00000262903.9	c.2514-4548A>G		intron_variant	Intron 22 of 23	1	NM_020771.4	ENSP00000262903.4

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84387 AN: 151744 Hom.: 25156 Cov.: 32

Gnomad AFR AF: 0.792

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.514

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

GnomAD4 genome AF: 0.556 AC: 84469 AN: 151860 Hom.: 25193 Cov.: 32 AF XY: 0.555 AC XY: 41189 AN XY: 74232

African (AFR) AF: 0.792 AC: 32853 AN: 41474

American (AMR) AF: 0.541 AC: 8263 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1348 AN: 3460

East Asian (EAS) AF: 0.423 AC: 2185 AN: 5160

South Asian (SAS) AF: 0.464 AC: 2238 AN: 4820

European-Finnish (FIN) AF: 0.475 AC: 4975 AN: 10468

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.456 AC: 30997 AN: 67912

Other (OTH) AF: 0.509 AC: 1069 AN: 2102

Alfa AF: 0.488 Hom.: 6469

Bravo AF: 0.575

Asia WGS AF: 0.408 AC: 1416 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.4
DANN	Benign	0.86
PhyloP100		0.18
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: rs7741733; hg19: chr6-105182839; COSMIC: COSV53506898; COSMIC: COSV53506898;