rs72218235

Variant names:

• chr6-104744232-TAAC-T
• rs72218235
• NM_020771.4:c.2443-5_2443-3delGTT

Your query was ambiguous. Multiple possible variants found:

• chr6-104744232-TAAC-T
• chr6-104744232-TAAC-TAACAAC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020771.4(HACE1):​c.2443-5_2443-3delGTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,575,176 control chromosomes in the GnomAD database, including 24,603 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4917 hom., cov: 26)
  • Exomes 𝑓: 0.15 (19686 hom.)
• Consequence: HACE1 NM_020771.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.25
• Publications: 2 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-104744232-TAAC-T is Benign according to our data. Variant chr6-104744232-TAAC-T is described in ClinVar as Benign. ClinVar VariationId is 1599999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 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.2443-5_2443-3delGTT		splice_region intron	N/A	NP_065822.2	Q8IYU2-1
	HACE1	NM_001321083.2		c.2341-5_2341-3delGTT		splice_region intron	N/A	NP_001308012.1
	HACE1	NM_001321080.2		c.2311-5_2311-3delGTT		splice_region 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.2443-5_2443-3delGTT		splice_region intron	N/A	ENSP00000262903.4	Q8IYU2-1
	HACE1	ENST00000369127.8	TSL:1	n.3464-5_3464-3delGTT		splice_region intron	N/A
	HACE1	ENST00000416605.6	TSL:1	n.*2105-5_*2105-3delGTT		splice_region intron	N/A	ENSP00000392425.2	E3W983

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34021 AN: 151752 Hom.: 4900 Cov.: 26

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.164 AC: 41071 AN: 250952 AF XY: 0.160

Gnomad AFR exome AF: 0.421

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.00495

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.155 AC: 220054 AN: 1423308 Hom.: 19686 AF XY: 0.155 AC XY: 110098 AN XY: 710576

African (AFR) AF: 0.418 AC: 13471 AN: 32198

American (AMR) AF: 0.178 AC: 7961 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4483 AN: 25868

East Asian (EAS) AF: 0.00563 AC: 222 AN: 39464

South Asian (SAS) AF: 0.163 AC: 13909 AN: 85452

European-Finnish (FIN) AF: 0.116 AC: 6193 AN: 53384

Middle Eastern (MID) AF: 0.232 AC: 1318 AN: 5672

European-Non Finnish (NFE) AF: 0.151 AC: 162857 AN: 1077576

Other (OTH) AF: 0.163 AC: 9640 AN: 59094

GnomAD4 genome AF: 0.224 AC: 34077 AN: 151868 Hom.: 4917 Cov.: 26 AF XY: 0.221 AC XY: 16372 AN XY: 74232

African (AFR) AF: 0.424 AC: 17517 AN: 41350

American (AMR) AF: 0.183 AC: 2786 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 610 AN: 3472

East Asian (EAS) AF: 0.00676 AC: 35 AN: 5180

South Asian (SAS) AF: 0.160 AC: 772 AN: 4820

European-Finnish (FIN) AF: 0.116 AC: 1230 AN: 10572

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.155 AC: 10512 AN: 67906

Other (OTH) AF: 0.200 AC: 423 AN: 2112

Alfa AF: 0.190 Hom.: 617

Bravo AF: 0.240

Asia WGS AF: 0.0930 AC: 321 AN: 3470

EpiCase AF: 0.164

EpiControl AF: 0.166

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Spastic paraplegia-severe developmental delay-epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72218235; hg19: chr6-105192107; COSMIC: COSV53502459;