chr14-73498221-T-A

Variant names:

• chr14-73498221-T-A
• rs777656399
• NM_001220484.1:c.2480A>T

Variant summary

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

The NM_001220484.1(HEATR4):​c.2480A>T​(p.Gln827Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: HEATR4 NM_001220484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2480A>T	p.Gln827Leu	missense	Exon 14 of 18	NP_001207413.1	Q86WZ0
	HEATR4	NM_203309.2		c.2480A>T	p.Gln827Leu	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.2480A>T	p.Gln827Leu	missense	Exon 14 of 18	ENSP00000450444.2	Q86WZ0
	HEATR4	ENST00000334988.2	TSL:1	c.2480A>T	p.Gln827Leu	missense	Exon 13 of 17	ENSP00000335447.2	Q86WZ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251436 AF XY: 0.0000294

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: 0.00000547 AC: 8 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

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	0.25
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0087	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.3
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.14
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.41		Gain of ubiquitination at K825 (P = 0.0605)
MVP		0.49
MPC		0.43
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.23
gMVP		0.35
Mutation Taster		=93/7	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: rs777656399; hg19: chr14-73964925;