chr1-180266593-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_033343.4(LHX4):c.450C>T(p.Asn150Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,830 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 265 hom., cov: 32)

Exomes 𝑓: 0.014 ( 286 hom. )

Consequence

LHX4
NM_033343.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0004384

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.769

Publications

12 publications found

Variant links:

Genes affected

LHX4 (HGNC:21734): (LIM homeobox 4) This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor involved in the control of differentiation and development of the pituitary gland. Mutations in this gene cause combined pituitary hormone deficiency 4. [provided by RefSeq, Dec 2010]

LHX4 Gene-Disease associations (from GenCC):

short stature-pituitary and cerebellar defects-small sella turcica syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypothyroidism due to deficient transcription factors involved in pituitary development or function
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pituitary stalk interruption syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LHX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 1-180266593-C-T is Benign according to our data. Variant chr1-180266593-C-T is described in ClinVar as [Benign]. Clinvar id is 262223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.769 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX4	NM_033343.4 link	c.450C>T	p.Asn150Asn	splice_region_variant, synonymous_variant	Exon 3 of 6	ENST00000263726.4	NP_203129.1	Q969G2A0A0S2Z5S4
LHX4	XM_011510105.3 link	c.267C>T	p.Asn89Asn	splice_region_variant, synonymous_variant	Exon 3 of 6		XP_011508407.1
LHX4	XM_011510106.4 link	c.267C>T	p.Asn89Asn	splice_region_variant, synonymous_variant	Exon 3 of 6		XP_011508408.1
LHX4	XM_011510108.3 link	c.225C>T	p.Asn75Asn	splice_region_variant, synonymous_variant	Exon 3 of 6		XP_011508410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4 link	c.450C>T	p.Asn150Asn	splice_region_variant, synonymous_variant	Exon 3 of 6	1	NM_033343.4	ENSP00000263726.2		Q969G2
LHX4	ENST00000561113.1 link	n.386C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000452783.1		H0YKF4

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5918

AN:

152112

Hom.:

261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.0146

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0272

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.0359

GnomAD2 exomes

AF:

0.0190

AC:

4763

AN:

250414

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.00918

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.0271

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0139

AC:

20282

AN:

1461602

Hom.:

286

Cov.:

AF XY:

0.0136

AC XY:

9878

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.101

AC:

3378

AN:

33472

American (AMR)

AF:

0.0102

AC:

455

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

392

AN:

26130

East Asian (EAS)

AF:

0.0193

AC:

767

AN:

39688

South Asian (SAS)

AF:

0.0172

AC:

1487

AN:

86222

European-Finnish (FIN)

AF:

0.0243

AC:

1298

AN:

53400

Middle Eastern (MID)

AF:

0.0210

AC:

121

AN:

5768

European-Non Finnish (NFE)

AF:

0.0101

AC:

11282

AN:

1111822

Other (OTH)

AF:

0.0182

AC:

1102

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1035

2070

3105

4140

5175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0391

AC:

5946

AN:

152228

Hom.:

265

Cov.:

AF XY:

0.0382

AC XY:

2844

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.104

AC:

4298

AN:

41508

American (AMR)

AF:

0.0182

AC:

279

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3472

East Asian (EAS)

AF:

0.0145

AC:

AN:

5178

South Asian (SAS)

AF:

0.0178

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0272

AC:

289

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

762

AN:

68000

Other (OTH)

AF:

0.0364

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

269

539

808

1078

1347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0193

Hom.:

312

Bravo

AF:

0.0402

Asia WGS

AF:

0.0350

AC:

123

AN:

3478

EpiCase

AF:

0.0122

EpiControl

AF:

0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 21, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Short stature-pituitary and cerebellar defects-small sella turcica syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.0

(source)

DANN

Benign

0.88

PhyloP100

-0.77

Mutation Taster

=74/26

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00044

dbscSNV1_RF

Benign

0.054

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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chr1-180266593-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over