14-31293337-A-G

Variant names:

• chr14-31293337-A-G
• NM_015473.4:c.6109T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015473.4(HEATR5A):​c.6109T>C​(p.Ser2037Pro) 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. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HEATR5A NM_015473.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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]

ENSG00000257831 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03790787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR5A	NM_015473.4	c.6109T>C	p.Ser2037Pro	missense_variant	Exon 36 of 36	ENST00000543095.7	NP_056288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEATR5A	ENST00000543095.7	c.6109T>C	p.Ser2037Pro	missense_variant	Exon 36 of 36	5	NM_015473.4	ENSP00000437968.2
HEATR5A	ENST00000538864.6	c.4765T>C	p.Ser1589Pro	missense_variant	Exon 28 of 28	5		ENSP00000439979.2
HEATR5A	ENST00000551414.1	n.2302T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
ENSG00000257831	ENST00000551799.1	n.401-2095A>G		intron_variant	Intron 4 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6109T>C (p.S2037P) alteration is located in exon 36 (coding exon 35) of the HEATR5A gene. This alteration results from a T to C substitution at nucleotide position 6109, causing the serine (S) at amino acid position 2037 to be replaced by a proline (P). 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	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	4.8	N
REVEL	Benign	0.062
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.083
MutPred		0.33		Loss of phosphorylation at S2037 (P = 0.0334);
MVP		0.040
ClinPred		0.18	T
GERP RS		1.9
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-31762543;