4-185019053-C-A

Variant names:

• chr4-185019053-C-A
• ENST00000338875.5:c.125C>A

Variant summary

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

The ENST00000338875.5(HELT):​c.125C>A​(p.Pro42Gln) 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. 13/17 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: HELT ENST00000338875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.107

Genes affected

HELT (HGNC:33783): (helt bHLH transcription factor) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anterior/posterior pattern specification; regulation of neurogenesis; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; regulation of transcription by RNA polymerase II; and suckling behavior. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.06089431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2	c.27+98C>A		intron_variant	Intron 1 of 3	ENST00000515777.6	NP_001287710.1
HELT	XM_017008186.2	c.125C>A	p.Pro42Gln	missense_variant	Exon 1 of 4		XP_016863675.2
HELT	NM_001300782.2	c.27+98C>A		intron_variant	Intron 1 of 3		NP_001287711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELT	ENST00000338875.5	c.125C>A	p.Pro42Gln	missense_variant	Exon 1 of 4	1		ENSP00000343464.4
HELT	ENST00000515777.6	c.27+98C>A		intron_variant	Intron 1 of 3	1	NM_001300781.2	ENSP00000426033.1
HELT	ENST00000505610.5	c.27+98C>A		intron_variant	Intron 1 of 3	1		ENSP00000422140.1
HELT	ENST00000513599.1	n.115+98C>A		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125C>A (p.P42Q) alteration is located in exon 1 (coding exon 1) of the HELT gene. This alteration results from a C to A substitution at nucleotide position 125, causing the proline (P) at amino acid position 42 to be replaced by a glutamine (Q). 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	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.65
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.0060
Sift	Benign	0.49	T
Sift4G	Benign	0.23	T
Vest4		0.22
MutPred		0.21		Loss of glycosylation at T45 (P = 0.0848);
MVP		0.11
MPC		1.0
ClinPred		0.036	T
GERP RS		-0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-185940207;