17-60046073-C-T

Variant names:

• chr17-60046073-C-T
• rs755692326
• NM_022070.5:c.2926G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022070.5(HEATR6):​c.2926G>A​(p.Ala976Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HEATR6 NM_022070.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69

Genes affected

HEATR6 (HGNC:24076): (HEAT repeat containing 6) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR6	NM_022070.5	c.2926G>A	p.Ala976Thr	missense_variant	Exon 19 of 20	ENST00000184956.11	NP_071353.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEATR6	ENST00000184956.11	c.2926G>A	p.Ala976Thr	missense_variant	Exon 19 of 20	1	NM_022070.5	ENSP00000184956.5
HEATR6	ENST00000587003.5	n.*1697G>A		non_coding_transcript_exon_variant	Exon 19 of 20	1		ENSP00000466192.1
HEATR6	ENST00000587003.5	n.*1697G>A		3_prime_UTR_variant	Exon 19 of 20	1		ENSP00000466192.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2926G>A (p.A976T) alteration is located in exon 19 (coding exon 19) of the HEATR6 gene. This alteration results from a G to A substitution at nucleotide position 2926, causing the alanine (A) at amino acid position 976 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.048	D
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0050	D;.;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.81		Gain of glycosylation at A976 (P = 0.1014);.;.;
MVP		0.87
MPC		0.55
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.49
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs755692326; hg19: chr17-58123434;