Genetic Variant BHLHE22:p.Ser90Ile (chr8-64581059-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152414.5(BHLHE22):c.269G>T(p.Ser90Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,325,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

BHLHE22
NM_152414.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.994

Variant links:

Genes affected

BHLHE22 (HGNC:11963): (basic helix-loop-helix family member e22) This gene encodes a protein that belongs to the basic helix-loop-helix (bHLH) family of transcription factors that regulate cell fate determination, proliferation, and differentiation. A similar protein in mouse is required for the development of the dorsal cochlear nuclei, and is thought to play a role in in the differentiation of neurons involved in sensory input. The mouse protein also functions in retinogenesis. [provided by RefSeq, Oct 2016]

BHLHE22 links:

BHLHE22-AS1 (HGNC:56147): (BHLHE22 antisense RNA 1)

BHLHE22-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09016296).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHE22	NM_152414.5 link	c.269G>T	p.Ser90Ile	missense_variant	Exon 1 of 1	ENST00000321870.3	NP_689627.1	Q8NFJ8B4DF88
BHLHE22-AS1	NR_152770.1 link	n.175+659C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BHLHE22	ENST00000321870.3 link	c.269G>T	p.Ser90Ile	missense_variant	Exon 1 of 1	6	NM_152414.5	ENSP00000318799.1	Q8NFJ8
BHLHE22-AS1	ENST00000517909.1 link	n.171+659C>A		intron_variant	Intron 1 of 1	2
BHLHE22-AS1	ENST00000665275.1 link	n.94+659C>A		intron_variant	Intron 1 of 1
BHLHE22-AS1	ENST00000670034.1 link	n.204+659C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000872

AC:

AN:

149010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000276

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.000488

GnomAD4 exome

AF:

0.00000680

AC:

AN:

1176786

Hom.:

Cov.:

AF XY:

0.00000704

AC XY:

AN XY:

568332

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

Gnomad4 AMR exome

AF:

0.000111

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:

0.00000204

Gnomad4 OTH exome

AF:

0.0000415

GnomAD4 genome

AF:

0.0000872

AC:

AN:

149102

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

72886

show subpopulations

Gnomad4 AFR

AF:

0.000275

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.000483

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.269G>T (p.S90I) alteration is located in exon 1 (coding exon 1) of the BHLHE22 gene. This alteration results from a G to T substitution at nucleotide position 269, causing the serine (S) at amino acid position 90 to be replaced by an isoleucine (I). 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

0.23

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.086

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.28

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.090

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.37

REVEL

Benign

0.28

Sift

Uncertain

0.0080

Sift4G

Benign

0.068

Polyphen

0.085

Vest4

0.22

MutPred

0.17

Loss of glycosylation at S90 (P = 0.0022);

MVP

0.30

MPC

1.1

ClinPred

0.20

GERP RS

2.1

Varity_R

0.098

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over