chr4-185019053-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 15/19 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
• Publications: 0 publications found

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]

ENSG00000301811 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06089431).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000338875.5. 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
	HELT	NM_001300781.2	MANE Select	c.27+98C>A		intron	N/A	NP_001287710.1	A6NFD8-3
	HELT	NM_001300782.2		c.27+98C>A		intron	N/A	NP_001287711.1	A6NFD8-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELT	ENST00000338875.5	TSL:1	c.125C>A	p.Pro42Gln	missense	Exon 1 of 4	ENSP00000343464.4	A0A087WSW0
	HELT	ENST00000515777.6	TSL:1 MANE Select	c.27+98C>A		intron	N/A	ENSP00000426033.1	A6NFD8-3
	HELT	ENST00000505610.5	TSL:1	c.27+98C>A		intron	N/A	ENSP00000422140.1	A6NFD8-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	0.085
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
PhyloP100		-0.11
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
PromoterAI		0.014	Neutral
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

hg19: chr4-185940207;