4-185019659-C-G

Variant names:

• chr4-185019659-C-G
• rs775257676
• ENST00000338875.5:c.300C>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.300C>G​(p.Ser100Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HELT ENST00000338875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• 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=0.09134662).

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.133-88C>G		intron	N/A	NP_001287710.1	A6NFD8-3
	HELT	NM_001300782.2		c.133-88C>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.300C>G	p.Ser100Arg	missense	Exon 3 of 4	ENSP00000343464.4	A0A087WSW0
	HELT	ENST00000515777.6	TSL:1 MANE Select	c.133-88C>G		intron	N/A	ENSP00000426033.1	A6NFD8-3
	HELT	ENST00000505610.5	TSL:1	c.133-88C>G		intron	N/A	ENSP00000422140.1	A6NFD8-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.9
DANN	Benign	0.92
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.12
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.0090
Sift	Benign	0.065	T
Sift4G	Uncertain	0.026	D
Vest4		0.15
MutPred		0.43		Loss of phosphorylation at S100 (P = 0.0221)
MVP		0.19
MPC		0.40
ClinPred		0.059	T
GERP RS		-0.61
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs775257676; hg19: chr4-185940813;