rs750371878

Variant names:

• chr6-104796666-G-A
• rs750371878
• NM_020771.4:c.805C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020771.4(HACE1):​c.805C>T​(p.Arg269*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000672 in 1,488,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: HACE1 NM_020771.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.51
• 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, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 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
• PP5: Variant 6-104796666-G-A is Pathogenic according to our data. Variant chr6-104796666-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 221295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.805C>T	p.Arg269*	stop_gained	Exon 9 of 24	NP_065822.2	Q8IYU2-1
	HACE1	NM_001321083.2		c.703C>T	p.Arg235*	stop_gained	Exon 9 of 24	NP_001308012.1
	HACE1	NM_001321080.2		c.673C>T	p.Arg225*	stop_gained	Exon 8 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.805C>T	p.Arg269*	stop_gained	Exon 9 of 24	ENSP00000262903.4	Q8IYU2-1
	HACE1	ENST00000416605.6	TSL:1	n.*362C>T		non_coding_transcript_exon	Exon 10 of 26	ENSP00000392425.2	E3W983
	HACE1	ENST00000416605.6	TSL:1	n.*362C>T		3_prime_UTR	Exon 10 of 26	ENSP00000392425.2	E3W983

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151660 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249890 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000598 AC: 8 AN: 1336766 Hom.: 0 Cov.: 22 AF XY: 0.00000744 AC XY: 5 AN XY: 672038

African (AFR) AF: 0.00 AC: 0 AN: 30734

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25362

East Asian (EAS) AF: 0.00 AC: 0 AN: 39044

South Asian (SAS) AF: 0.0000478 AC: 4 AN: 83612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00000400 AC: 4 AN: 999504

Other (OTH) AF: 0.00 AC: 0 AN: 56270

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151660 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74002

African (AFR) AF: 0.00 AC: 0 AN: 41262

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Intellectual disability (1)
1	-	-	Seizure;C0557874:Global developmental delay;C1858120:Generalized hypotonia (1)
1	-	-	Spastic paraplegia-severe developmental delay-epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		3.5
Vest4		0.94
GERP RS		5.6
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs750371878; hg19: chr6-105244541;