chr4-185019020-G-T

Variant names:

• chr4-185019020-G-T
• rs144613350
• ENST00000338875.5:c.92G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000338875.5(HELT):​c.92G>T​(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,988 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: HELT ENST00000338875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.14
• Publications: 3 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010385871).

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+65G>T		intron	N/A	NP_001287710.1	A6NFD8-3
	HELT	NM_001300782.2		c.27+65G>T		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.92G>T	p.Arg31Leu	missense	Exon 1 of 4	ENSP00000343464.4	A0A087WSW0
	HELT	ENST00000515777.6	TSL:1 MANE Select	c.27+65G>T		intron	N/A	ENSP00000426033.1	A6NFD8-3
	HELT	ENST00000505610.5	TSL:1	c.27+65G>T		intron	N/A	ENSP00000422140.1	A6NFD8-4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251054 AF XY: 0.000221

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.000158 AC XY: 115 AN XY: 727094

African (AFR) AF: 0.000926 AC: 31 AN: 33470

American (AMR) AF: 0.000157 AC: 7 AN: 44696

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53414

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5738

European-Non Finnish (NFE) AF: 0.000115 AC: 128 AN: 1111898

Other (OTH) AF: 0.000282 AC: 17 AN: 60386

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74508

African (AFR) AF: 0.000793 AC: 33 AN: 41598

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000164

EpiControl AF: 0.000237

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	0.099
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.90
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.0050
Sift	Benign	0.57	T
Sift4G	Uncertain	0.056	T
Vest4		0.24
MVP		0.085
MPC		0.42
ClinPred		0.0045	T
GERP RS		-1.6
PromoterAI		-0.033	Neutral
Mutation Taster		=98/2	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: rs144613350; hg19: chr4-185940174;