4-185019023-A-G

Variant names:

• chr4-185019023-A-G
• rs867377493
• ENST00000338875.5:c.95A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000338875.5(HELT):​c.95A>G​(p.His32Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H32P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HELT ENST00000338875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07235253).

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+68A>G		intron	N/A	NP_001287710.1	A6NFD8-3
	HELT	NM_001300782.2		c.27+68A>G		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.95A>G	p.His32Arg	missense	Exon 1 of 4	ENSP00000343464.4	A0A087WSW0
	HELT	ENST00000515777.6	TSL:1 MANE Select	c.27+68A>G		intron	N/A	ENSP00000426033.1	A6NFD8-3
	HELT	ENST00000505610.5	TSL:1	c.27+68A>G		intron	N/A	ENSP00000422140.1	A6NFD8-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.52
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.27
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.0090
Sift	Benign	0.52	T
Sift4G	Uncertain	0.048	D
Vest4		0.23
MutPred		0.13		Loss of glycosylation at T30 (P = 0.1255)
MVP		0.061
MPC		0.41
ClinPred		0.038	T
GERP RS		-6.1
PromoterAI		0.031	Neutral
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs867377493; hg19: chr4-185940177;