1-180266593-C-T

Variant names:

• chr1-180266593-C-T
• rs16855642
• NM_033343.4:c.450C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr1-180266593-C-T is described in Lovd as [Benign]. Variant chr1-180266593-C-T is described in Lovd as [Likely_benign].
• 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	c.450C>T	p.Asn150Asn	splice_region_variant, synonymous_variant	Exon 3 of 6	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.267C>T	p.Asn89Asn	splice_region_variant, synonymous_variant	Exon 3 of 6		XP_011508407.1
LHX4	XM_011510106.4	c.267C>T	p.Asn89Asn	splice_region_variant, synonymous_variant	Exon 3 of 6		XP_011508408.1
LHX4	XM_011510108.3	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	c.450C>T	p.Asn150Asn	splice_region_variant, synonymous_variant	Exon 3 of 6	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000561113.1	n.386C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000452783.1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5918 AN: 152112 Hom.: 261 Cov.: 32

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

GnomAD3 exomes AF: 0.0190 AC: 4763 AN: 250414 Hom.: 120 AF XY: 0.0173 AC XY: 2343 AN XY: 135440

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 SAS exome AF: 0.0175

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.: 32 AF XY: 0.0136 AC XY: 9878 AN XY: 727088

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.0193

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.0243

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0391 AC: 5946 AN: 152228 Hom.: 265 Cov.: 32 AF XY: 0.0382 AC XY: 2844 AN XY: 74438

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0161 Hom.: 106

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

Submissions by phenotype

not provided Benign:4

-

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

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

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

Apr 21, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

- -

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
DANN	Benign	0.88

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

LitVar

Other links and lift over

dbSNP: rs16855642; hg19: chr1-180235728;