4-185019729-C-G

Variant names:

• chr4-185019729-C-G
• rs200914502
• ENST00000338875.5:c.370C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000338875.5(HELT):​c.370C>G​(p.Pro124Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,612,948 control chromosomes in the GnomAD database, including 2 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P124L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: HELT ENST00000338875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.773

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044222564).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2	c.133-18C>G		intron_variant	Intron 2 of 3	ENST00000515777.6	NP_001287710.1
HELT	NM_001300782.2	c.133-18C>G		intron_variant	Intron 2 of 3		NP_001287711.1
HELT	XM_017008186.2	c.301-18C>G		intron_variant	Intron 2 of 3		XP_016863675.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELT	ENST00000338875.5	c.370C>G	p.Pro124Ala	missense_variant	Exon 3 of 4	1		ENSP00000343464.4
HELT	ENST00000515777.6	c.133-18C>G		intron_variant	Intron 2 of 3	1	NM_001300781.2	ENSP00000426033.1
HELT	ENST00000505610.5	c.133-18C>G		intron_variant	Intron 2 of 3	1		ENSP00000422140.1
HELT	ENST00000513599.1	n.458C>G		non_coding_transcript_exon_variant	Exon 2 of 3	1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000287 AC: 71 AN: 247056 Hom.: 0 AF XY: 0.000320 AC XY: 43 AN XY: 134456

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000987

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000342

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.000251 AC: 366 AN: 1460598 Hom.: 2 Cov.: 32 AF XY: 0.000256 AC XY: 186 AN XY: 726576

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000760

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74494

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370C>G (p.P124A) alteration is located in exon 3 (coding exon 3) of the HELT gene. This alteration results from a C to G substitution at nucleotide position 370, causing the proline (P) at amino acid position 124 to be replaced by an alanine (A). 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	-0.46	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.5
DANN	Benign	0.97
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.0060
Sift	Uncertain	0.019	D
Sift4G	Benign	0.22	T
Vest4		0.15
MVP		0.15
MPC		0.34
ClinPred		0.010	T
GERP RS		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200914502; hg19: chr4-185940883;