6-104784358-A-C

Variant names:

• chr6-104784358-A-C
• rs9322817
• NM_020771.4:c.1478+59T>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.1478+59T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,140,862 control chromosomes in the GnomAD database, including 79,259 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 0.42 (14207 hom., cov: 31)
  • Exomes 𝑓: 0.36 (65052 hom.)
• Consequence: HACE1 NM_020771.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.946
• Publications: 24 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 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.1478+59T>G		intron	N/A	NP_065822.2
	HACE1	NM_001321083.2		c.1376+59T>G		intron	N/A	NP_001308012.1
	HACE1	NM_001321080.2		c.1346+59T>G		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.1478+59T>G		intron	N/A	ENSP00000262903.4
	HACE1	ENST00000369127.8	TSL:1	n.2499+59T>G		intron	N/A
	HACE1	ENST00000416605.6	TSL:1	n.*1035+59T>G		intron	N/A	ENSP00000392425.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63375 AN: 151798 Hom.: 14188 Cov.: 31

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.358 AC: 354001 AN: 988946 Hom.: 65052 Cov.: 13 AF XY: 0.357 AC XY: 183111 AN XY: 513542

African (AFR) AF: 0.598 AC: 14468 AN: 24182

American (AMR) AF: 0.371 AC: 16327 AN: 43956

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 6673 AN: 23250

East Asian (EAS) AF: 0.254 AC: 9514 AN: 37518

South Asian (SAS) AF: 0.333 AC: 25541 AN: 76686

European-Finnish (FIN) AF: 0.321 AC: 17059 AN: 53162

Middle Eastern (MID) AF: 0.408 AC: 1991 AN: 4876

European-Non Finnish (NFE) AF: 0.362 AC: 245963 AN: 680376

Other (OTH) AF: 0.366 AC: 16465 AN: 44940

GnomAD4 genome AF: 0.418 AC: 63449 AN: 151916 Hom.: 14207 Cov.: 31 AF XY: 0.412 AC XY: 30570 AN XY: 74242

African (AFR) AF: 0.591 AC: 24488 AN: 41426

American (AMR) AF: 0.382 AC: 5824 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 989 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1382 AN: 5160

South Asian (SAS) AF: 0.307 AC: 1481 AN: 4820

European-Finnish (FIN) AF: 0.326 AC: 3438 AN: 10532

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24551 AN: 67952

Other (OTH) AF: 0.389 AC: 820 AN: 2108

Alfa AF: 0.391 Hom.: 22669

Bravo AF: 0.433

Asia WGS AF: 0.257 AC: 897 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		0.95
PromoterAI		-0.00060	Neutral
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: rs9322817; hg19: chr6-105232233; COSMIC: COSV53500225; COSMIC: COSV53500225;