4-185020351-C-A

Variant names:

• chr4-185020351-C-A
• NM_001300781.2:c.308C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001300781.2(HELT):​c.308C>A​(p.Thr103Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HELT NM_001300781.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2	c.308C>A	p.Thr103Asn	missense_variant	Exon 4 of 4	ENST00000515777.6	NP_001287710.1
HELT	NM_001300782.2	c.305C>A	p.Thr102Asn	missense_variant	Exon 4 of 4		NP_001287711.1
HELT	XM_017008186.2	c.476C>A	p.Thr159Asn	missense_variant	Exon 4 of 4		XP_016863675.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELT	ENST00000515777.6	c.308C>A	p.Thr103Asn	missense_variant	Exon 4 of 4	1	NM_001300781.2	ENSP00000426033.1
HELT	ENST00000338875.5	c.563C>A	p.Thr188Asn	missense_variant	Exon 4 of 4	1		ENSP00000343464.4
HELT	ENST00000505610.5	c.305C>A	p.Thr102Asn	missense_variant	Exon 4 of 4	1		ENSP00000422140.1
HELT	ENST00000513599.1	n.648C>A		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.563C>A (p.T188N) alteration is located in exon 4 (coding exon 4) of the HELT gene. This alteration results from a C to A substitution at nucleotide position 563, causing the threonine (T) at amino acid position 188 to be replaced by an asparagine (N). 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
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.70	T
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.049	D;D;T
Vest4		0.93
MutPred		0.38		.;.;Loss of loop (P = 0.1242);
MVP		0.78
MPC		1.2
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.59

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-185941505;