6-104744191-T-A

Variant names:

• chr6-104744191-T-A
• NM_020771.4:c.2482A>T
• HACE1 p.Arg828*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020771.4(HACE1):​c.2482A>T​(p.Arg828*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HACE1 NM_020771.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.124
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.2482A>T	p.Arg828*	stop_gained	Exon 22 of 24	NP_065822.2	Q8IYU2-1
	HACE1	NM_001321083.2		c.2380A>T	p.Arg794*	stop_gained	Exon 22 of 24	NP_001308012.1
	HACE1	NM_001321080.2		c.2350A>T	p.Arg784*	stop_gained	Exon 21 of 23	NP_001308009.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACE1	ENST00000262903.9	TSL:1 MANE Select	c.2482A>T	p.Arg828*	stop_gained	Exon 22 of 24	ENSP00000262903.4	Q8IYU2-1
	HACE1	ENST00000369127.8	TSL:1	n.3503A>T		non_coding_transcript_exon	Exon 11 of 13
	HACE1	ENST00000416605.6	TSL:1	n.*2144A>T		non_coding_transcript_exon	Exon 24 of 26	ENSP00000392425.2	E3W983

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		0.12
Mutation Taster		=12/188	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-105192066;