Genetic Variant BHLHE22:p.Ala173Val (chr8-64581308-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152414.5(BHLHE22):c.518C>T(p.Ala173Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000671 in 1,429,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

BHLHE22
NM_152414.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.363

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061368734).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHE22	NM_152414.5 link	c.518C>T	p.Ala173Val	missense_variant	Exon 1 of 1	ENST00000321870.3	NP_689627.1	Q8NFJ8B4DF88
BHLHE22-AS1	NR_152770.1 link	n.175+410G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BHLHE22	ENST00000321870.3 link	c.518C>T	p.Ala173Val	missense_variant	Exon 1 of 1	6	NM_152414.5	ENSP00000318799.1	Q8NFJ8
BHLHE22-AS1	ENST00000517909.1 link	n.171+410G>A		intron_variant	Intron 1 of 1	2
BHLHE22-AS1	ENST00000665275.1 link	n.94+410G>A		intron_variant	Intron 1 of 1
BHLHE22-AS1	ENST00000670034.1 link	n.204+410G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000661

AC:

AN:

151360

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000274

AC:

AN:

36506

Hom.:

AF XY:

0.000377

AC XY:

AN XY:

21206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000352

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000516

Gnomad NFE exome

AF:

0.000424

Gnomad OTH exome

AF:

0.000967

GnomAD4 exome

AF:

0.0000673

AC:

AN:

1278288

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

626646

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000529

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000970

Gnomad4 NFE exome

AF:

0.0000752

Gnomad4 OTH exome

AF:

0.0000378

GnomAD4 genome

AF:

0.0000661

AC:

AN:

151360

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73952

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.518C>T (p.A173V) alteration is located in exon 1 (coding exon 1) of the BHLHE22 gene. This alteration results from a C to T substitution at nucleotide position 518, causing the alanine (A) at amino acid position 173 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.53

REVEL

Benign

0.25

Sift

Uncertain

0.013

Sift4G

Benign

0.39

Polyphen

0.18

Vest4

0.13

MutPred

0.24

Gain of relative solvent accessibility (P = 0.005);

MVP

0.19

MPC

1.0

ClinPred

0.041

GERP RS

2.6

Varity_R

0.11

gMVP

0.23

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