12-26122151-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030762.3(BHLHE41):c.1364T>G(p.Leu455Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,394,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

BHLHE41 (HGNC:16617): (basic helix-loop-helix family member e41) This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL's transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation. Defects in this gene are associated with the short sleep phenotype. [provided by RefSeq, Feb 2014]

SSPN (HGNC:11322): (sarcospan) This gene encodes a member of the dystrophin-glycoprotein complex (DGC). The DGC spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Two alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25242358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHLHE41	NM_030762.3	c.1364T>G	p.Leu455Arg	missense_variant	5/5	ENST00000242728.5
SSPN	XM_011520853.4	c.-32A>C		splice_region_variant, 5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHLHE41	ENST00000242728.5	c.1364T>G	p.Leu455Arg	missense_variant	5/5	1	NM_030762.3	P1
SSPN	ENST00000538142.5	c.-32A>C		splice_region_variant, 5_prime_UTR_variant	1/3	4
SSPN	ENST00000534829.5	n.100A>C		splice_region_variant, non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000211 AC: 3 AN: 142436 Hom.: 0 AF XY: 0.0000259 AC XY: 2 AN XY: 77306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000289

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394106 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 687470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000283

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The c.1364T>G (p.L455R) alteration is located in exon 5 (coding exon 5) of the BHLHE41 gene. This alteration results from a T to G substitution at nucleotide position 1364, causing the leucine (L) at amino acid position 455 to be replaced by an arginine (R). 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	Benign	0.097
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Polyphen		0.99	D
Vest4		0.36
MutPred		0.29		Gain of catalytic residue at R452 (P = 0.0213);
MVP		0.57
ClinPred		0.65	D
GERP RS		1.4
Varity_R		0.47
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1330625550; hg19: chr12-26275084;