12-26122622-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_030762.3(BHLHE41):c.893C>T(p.Ala298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,179,890 control chromosomes in the GnomAD database, including 131,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (12182 hom., cov: 29)
  • Exomes 𝑓: 0.48 (119019 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.298

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.2464648E-6).
• BP6: Variant 12-26122622-G-A is Benign according to our data. Variant chr12-26122622-G-A is described in ClinVar as [Benign]. Clinvar id is 3057054.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHLHE41	NM_030762.3	c.893C>T	p.Ala298Val	missense_variant	5/5	ENST00000242728.5
SSPN	XM_011520853.4	c.-31+470G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHLHE41	ENST00000242728.5	c.893C>T	p.Ala298Val	missense_variant	5/5	1	NM_030762.3	P1
SSPN	ENST00000538142.5	c.-31+470G>A		intron_variant		4
SSPN	ENST00000534829.5	n.101+470G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.381 AC: 55537 AN: 145614 Hom.: 12175 Cov.: 29

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.393

GnomAD3 exomes AF: 0.527 AC: 3171 AN: 6020 Hom.: 850 AF XY: 0.529 AC XY: 1948 AN XY: 3684

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.663

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.773

Gnomad SAS exome AF: 0.427

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.486

GnomAD4 exome AF: 0.476 AC: 492131 AN: 1034162 Hom.: 119019 Cov.: 34 AF XY: 0.476 AC XY: 233930 AN XY: 491638

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.600

Gnomad4 ASJ exome AF: 0.420

Gnomad4 EAS exome AF: 0.524

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.503

Gnomad4 NFE exome AF: 0.487

Gnomad4 OTH exome AF: 0.460

GnomAD4 genome AF: 0.381 AC: 55552 AN: 145728 Hom.: 12182 Cov.: 29 AF XY: 0.378 AC XY: 26843 AN XY: 70928

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.501

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.395

Alfa AF: 0.433 Hom.: 1877

Bravo AF: 0.382

ExAC AF: 0.150 AC: 3144

Asia WGS AF: 0.348 AC: 1130 AN: 3246

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BHLHE41-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000052	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.049
Sift	Benign	0.15	T
Sift4G	Benign	0.13	T
Polyphen		0.051	B
Vest4		0.037
ClinPred		0.0078	T
GERP RS		1.4
Varity_R		0.044
gMVP		0.33

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: rs11048413; hg19: chr12-26275555; COSMIC: COSV54378221; COSMIC: COSV54378221;