NM_020771.4:c.2513+221G>A

Variant names:

• chr6-104743939-C-T
• rs6942231
• NM_020771.4:c.2513+221G>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.2513+221G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 151,866 control chromosomes in the GnomAD database, including 17,858 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 (17858 hom., cov: 32)
• Consequence: HACE1 NM_020771.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.713 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.2513+221G>A		intron	N/A	NP_065822.2
	HACE1	NM_001321083.2		c.2411+221G>A		intron	N/A	NP_001308012.1
	HACE1	NM_001321080.2		c.2381+221G>A		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.2513+221G>A		intron	N/A	ENSP00000262903.4
	HACE1	ENST00000369127.8	TSL:1	n.3534+221G>A		intron	N/A
	HACE1	ENST00000416605.6	TSL:1	n.*2175+221G>A		intron	N/A	ENSP00000392425.2

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69004 AN: 151748 Hom.: 17820 Cov.: 32

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.455 AC: 69095 AN: 151866 Hom.: 17858 Cov.: 32 AF XY: 0.448 AC XY: 33254 AN XY: 74214

African (AFR) AF: 0.720 AC: 29813 AN: 41434

American (AMR) AF: 0.392 AC: 5989 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1029 AN: 3466

East Asian (EAS) AF: 0.265 AC: 1374 AN: 5176

South Asian (SAS) AF: 0.312 AC: 1507 AN: 4824

European-Finnish (FIN) AF: 0.328 AC: 3449 AN: 10508

Middle Eastern (MID) AF: 0.401 AC: 117 AN: 292

European-Non Finnish (NFE) AF: 0.362 AC: 24593 AN: 67882

Other (OTH) AF: 0.411 AC: 867 AN: 2108

Alfa AF: 0.396 Hom.: 24917

Bravo AF: 0.474

Asia WGS AF: 0.260 AC: 902 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.032
DANN	Benign	0.19
PhyloP100		-1.3
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: rs6942231; hg19: chr6-105191814; COSMIC: COSV53500417;