Genetic Variant HLX:p.Pro356Leu (chr1-220884304-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021958.4(HLX):c.1067C>T(p.Pro356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,612,712 control chromosomes in the GnomAD database, including 90,502 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.36 ( 10122 hom., cov: 31)

Exomes 𝑓: 0.33 ( 80380 hom. )

Consequence

HLX
NM_021958.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.613

Variant links:

Genes affected

HLX (HGNC:4978): (H2.0 like homeobox) Enables sequence-specific DNA binding activity. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including animal organ development; enteric nervous system development; and regulation of T-helper cell differentiation. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

HLX links:

ENSG00000286231 (HGNC:):

ENSG00000286231 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010964274).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLX	NM_021958.4 link	c.1067C>T	p.Pro356Leu	missense_variant	Exon 4 of 4	ENST00000366903.8	NP_068777.1	Q14774

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HLX	ENST00000366903.8 link	c.1067C>T	p.Pro356Leu	missense_variant	Exon 4 of 4	1	NM_021958.4	ENSP00000355870.5	Q14774
ENSG00000286231	ENST00000651706.1 link	n.*375C>T		non_coding_transcript_exon_variant	Exon 9 of 9			ENSP00000499157.1	A0A494C1P3
ENSG00000286231	ENST00000651706.1 link	n.*375C>T		3_prime_UTR_variant	Exon 9 of 9			ENSP00000499157.1	A0A494C1P3

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54189

AN:

151600

Hom.:

10108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.446

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.456

Gnomad EAS

AF:

0.0910

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.366

Gnomad MID

AF:

0.372

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.345

GnomAD3 exomes

AF:

0.312

AC:

77785

AN:

249472

Hom.:

13126

AF XY:

0.311

AC XY:

42002

AN XY:

134952

show subpopulations

Gnomad AFR exome

AF:

0.443

Gnomad AMR exome

AF:

0.272

Gnomad ASJ exome

AF:

0.450

Gnomad EAS exome

AF:

0.0575

Gnomad SAS exome

AF:

0.254

Gnomad FIN exome

AF:

0.360

Gnomad NFE exome

AF:

0.339

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.327

AC:

477595

AN:

1460992

Hom.:

80380

Cov.:

AF XY:

0.325

AC XY:

236385

AN XY:

726712

show subpopulations

Gnomad4 AFR exome

AF:

0.447

Gnomad4 AMR exome

AF:

0.279

Gnomad4 ASJ exome

AF:

0.447

Gnomad4 EAS exome

AF:

0.106

Gnomad4 SAS exome

AF:

0.257

Gnomad4 FIN exome

AF:

0.355

Gnomad4 NFE exome

AF:

0.333

Gnomad4 OTH exome

AF:

0.335

GnomAD4 genome

AF:

0.357

AC:

54237

AN:

151720

Hom.:

10122

Cov.:

AF XY:

0.352

AC XY:

26107

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.446

Gnomad4 AMR

AF:

0.309

Gnomad4 ASJ

AF:

0.456

Gnomad4 EAS

AF:

0.0905

Gnomad4 SAS

AF:

0.245

Gnomad4 FIN

AF:

0.366

Gnomad4 NFE

AF:

0.337

Gnomad4 OTH

AF:

0.342

Alfa

AF:

0.336

Hom.:

20677

Bravo

AF:

0.358

TwinsUK

AF:

0.334

AC:

1239

ALSPAC

AF:

0.325

AC:

1251

ESP6500AA

AF:

0.428

AC:

1884

ESP6500EA

AF:

0.351

AC:

3017

ExAC

AF:

0.315

AC:

38176

Asia WGS

AF:

0.201

AC:

702

AN:

3478

EpiCase

AF:

0.351

EpiControl

AF:

0.353

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0011

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.020

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.36

T;T

Polyphen

0.069

B;.

Vest4

0.041

MPC

0.48

ClinPred

0.0064

GERP RS

2.0

Varity_R

0.044

gMVP

0.38

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over