14-73498168-C-T

Variant names:

• chr14-73498168-C-T
• rs769983717
• NM_001220484.1:c.2533G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001220484.1(HEATR4):​c.2533G>A​(p.Asp845Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,611,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HEATR4 NM_001220484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• Publications: 3 publications found

Genes affected

HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

ACOT1 (HGNC:33128): (acyl-CoA thioesterase 1) Enables acyl-CoA hydrolase activity. Involved in acyl-CoA metabolic process; long-chain fatty acid metabolic process; and very long-chain fatty acid metabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15408003).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001220484.1. 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
	HEATR4	NM_001220484.1	MANE Select	c.2533G>A	p.Asp845Asn	missense	Exon 14 of 18	NP_001207413.1	Q86WZ0
	HEATR4	NM_203309.2		c.2533G>A	p.Asp845Asn	missense	Exon 13 of 17	NP_976054.2	Q86WZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEATR4	ENST00000553558.6	TSL:2 MANE Select	c.2533G>A	p.Asp845Asn	missense	Exon 14 of 18	ENSP00000450444.2	Q86WZ0
	HEATR4	ENST00000334988.2	TSL:1	c.2533G>A	p.Asp845Asn	missense	Exon 13 of 17	ENSP00000335447.2	Q86WZ0

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152090 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250604 AF XY: 0.0000148

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: 0.00000884

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1459580 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 725702

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110352

Other (OTH) AF: 0.0000830 AC: 5 AN: 60276

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.043
Sift	Benign	0.13	T
Sift4G	Uncertain	0.019	D
Polyphen		0.14	B
Vest4		0.28
MutPred		0.35		Gain of catalytic residue at D845 (P = 0.038)
MVP		0.23
MPC		0.27
ClinPred		0.57	D
GERP RS		4.2
Varity_R		0.081
gMVP		0.15
Mutation Taster		=95/5	polymorphism

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: rs769983717; hg19: chr14-73964872; COSMIC: COSV58373810; COSMIC: COSV58373810;