Genetic Variant NM_030762.3:c.1168C>A (chr12-26122347-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_030762.3(BHLHE41):c.1168C>A(p.Pro390Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000087 in 1,034,432 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P390S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

BHLHE41
NM_030762.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.42

Publications

0 publications found

Variant links:

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]

BHLHE41 links:

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]

SSPN links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030762.3. 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
	BHLHE41	NM_030762.3	MANE Select	c.1168C>A	p.Pro390Thr	missense	Exon 5 of 5	NP_110389.1	Q9C0J9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BHLHE41	ENST00000242728.5	TSL:1 MANE Select	c.1168C>A	p.Pro390Thr	missense	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
BHLHE41	ENST00000957109.1		c.1174C>A	p.Pro392Thr	missense	Exon 5 of 5	ENSP00000627168.1
SSPN	ENST00000538142.5	TSL:4	c.-31+195G>T		intron	N/A	ENSP00000445360.1	F5H381

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000870

AC:

AN:

1034432

Hom.:

Cov.:

AF XY:

0.00000408

AC XY:

AN XY:

490130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20882

American (AMR)

AF:

0.00

AC:

AN:

6782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11734

East Asian (EAS)

AF:

0.00

AC:

AN:

21776

South Asian (SAS)

AF:

0.00

AC:

AN:

19548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2692

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

890622

Other (OTH)

AF:

0.00

AC:

AN:

39738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.81

PhyloP100

6.4

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Polyphen

0.97

Vest4

0.48

MutPred

0.45

Gain of catalytic residue at Y389 (P = 5e-04)

MVP

0.60

ClinPred

0.93

GERP RS

3.1

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.58

gMVP

0.71

Mutation Taster

=49/51

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over