Genetic Variant NM_021958.4:c.346T>C (chr1-220880203-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021958.4(HLX):c.346T>C(p.Ser116Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,612,368 control chromosomes in the GnomAD database, including 47,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4161 hom., cov: 33)

Exomes 𝑓: 0.24 ( 43156 hom. )

Consequence

HLX
NM_021958.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Publications

24 publications found

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:

HLX-AS1 (HGNC:42509): (HLX antisense RNA 1)

HLX-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001368612).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021958.4. 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
	HLX	NM_021958.4	MANE Select	c.346T>C	p.Ser116Pro	missense	Exon 1 of 4	NP_068777.1	Q14774
	HLX-AS1	NR_046901.1		n.-63A>G		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLX	ENST00000366903.8	TSL:1 MANE Select	c.346T>C	p.Ser116Pro	missense	Exon 1 of 4	ENSP00000355870.5	Q14774
ENSG00000286231	ENST00000651706.1		n.843-991T>C		intron	N/A	ENSP00000499157.1	A0A494C1P3
HLX	ENST00000944514.1		c.346T>C	p.Ser116Pro	missense	Exon 1 of 4	ENSP00000614573.1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34929

AN:

151988

Hom.:

4153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.176

Gnomad EAS

AF:

0.218

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.313

Gnomad MID

AF:

0.191

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.218

GnomAD2 exomes

AF:

0.244

AC:

59203

AN:

242226

AF XY:

0.238

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.174

Gnomad EAS exome

AF:

0.229

Gnomad FIN exome

AF:

0.306

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.229

GnomAD4 exome

AF:

0.240

AC:

350889

AN:

1460262

Hom.:

43156

Cov.:

AF XY:

0.238

AC XY:

172835

AN XY:

726452

show subpopulations

African (AFR)

AF:

0.182

AC:

6078

AN:

33458

American (AMR)

AF:

0.317

AC:

14159

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4581

AN:

26102

East Asian (EAS)

AF:

0.195

AC:

7721

AN:

39680

South Asian (SAS)

AF:

0.196

AC:

16920

AN:

86236

European-Finnish (FIN)

AF:

0.306

AC:

16206

AN:

52892

Middle Eastern (MID)

AF:

0.179

AC:

1028

AN:

5758

European-Non Finnish (NFE)

AF:

0.243

AC:

270396

AN:

1111302

Other (OTH)

AF:

0.229

AC:

13800

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

17005

34010

51015

68020

85025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9224

18448

27672

36896

46120

<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

AF:

0.230

AC:

34958

AN:

152106

Hom.:

4161

Cov.:

AF XY:

0.234

AC XY:

17369

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.188

AC:

7794

AN:

41492

American (AMR)

AF:

0.256

AC:

3913

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

609

AN:

3468

East Asian (EAS)

AF:

0.218

AC:

1122

AN:

5152

South Asian (SAS)

AF:

0.196

AC:

949

AN:

4830

European-Finnish (FIN)

AF:

0.313

AC:

3310

AN:

10570

Middle Eastern (MID)

AF:

0.202

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.242

AC:

16477

AN:

67978

Other (OTH)

AF:

0.214

AC:

451

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1433

2867

4300

5734

7167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.241

Hom.:

7133

Bravo

AF:

0.226

ESP6500AA

AF:

0.193

AC:

846

ESP6500EA

AF:

0.222

AC:

1904

ExAC

AF:

0.233

AC:

28129

Asia WGS

AF:

0.184

AC:

639

AN:

3472

EpiCase

AF:

0.230

EpiControl

AF:

0.227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0014

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

PhyloP100

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.3

REVEL

Benign

0.028

Sift

Benign

0.086

Sift4G

Benign

0.36

Polyphen

0.048

Vest4

0.065

MPC

0.58

ClinPred

0.0053

GERP RS

3.4

Varity_R

0.25

gMVP

0.47

Mutation Taster

=93/7

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over