Genetic Variant HEATR5A:p.Pro1891Leu (chr14-31294052-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015473.4(HEATR5A):c.5672C>T(p.Pro1891Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HEATR5A
NM_015473.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

Variant links:

Genes affected

HEATR5A (HGNC:20276): (HEAT repeat containing 5A) Predicted to be involved in endocytosis; protein localization; and retrograde transport, endosome to Golgi. Predicted to be located in cytosol. Predicted to be active in endocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

HEATR5A links:

ENSG00000257831 (HGNC:):

ENSG00000257831 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR5A	NM_015473.4 link	c.5672C>T	p.Pro1891Leu	missense_variant	Exon 35 of 36	ENST00000543095.7	NP_056288.2	Q86XA9F5H619

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEATR5A	ENST00000543095.7 link	c.5672C>T	p.Pro1891Leu	missense_variant	Exon 35 of 36	5	NM_015473.4	ENSP00000437968.2	F5H619
HEATR5A	ENST00000538864.6 link	c.4328C>T	p.Pro1443Leu	missense_variant	Exon 27 of 28	5		ENSP00000439979.2	H7C5W6
HEATR5A	ENST00000551414.1 link	n.1865C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
ENSG00000257831	ENST00000551799.1 link	n.401-1380G>A		intron_variant	Intron 4 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720356

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5672C>T (p.P1891L) alteration is located in exon 35 (coding exon 34) of the HEATR5A gene. This alteration results from a C to T substitution at nucleotide position 5672, causing the proline (P) at amino acid position 1891 to be replaced by a leucine (L). 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

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.020

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.036

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.88

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

REVEL

Benign

0.066

Sift

Benign

0.28

Sift4G

Benign

0.26

Vest4

0.23

MutPred

0.48

Loss of loop (P = 0.1242);

MVP

0.48

ClinPred

0.86

GERP RS

5.2

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: -33

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over