1-180230592-T-C

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.63T>C(p.Gly21=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,613,584 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (48 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (334 hom.)
• Consequence: LHX4 NM_033343.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.338

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=-0.57).
• BP6: Variant 1-180230592-T-C is Benign according to our data. Variant chr1-180230592-T-C is described in ClinVar as [Benign]. Clinvar id is 293858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-180230592-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.338 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX4	NM_033343.4	c.63T>C	p.Gly21=	synonymous_variant	1/6	ENST00000263726.4
LHX4	XM_011510105.3	c.-108+1679T>C		intron_variant
LHX4	XM_011510106.4	c.-108+1439T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX4	ENST00000263726.4	c.63T>C	p.Gly21=	synonymous_variant	1/6	1	NM_033343.4	P1
LHX4	ENST00000558139.1	n.295T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 919 AN: 152110 Hom.: 48 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0121 AC: 3022 AN: 250626 Hom.: 146 AF XY: 0.0109 AC XY: 1482 AN XY: 135724

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.00887

Gnomad NFE exome AF: 0.000751

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00465 AC: 6800 AN: 1461358 Hom.: 334 Cov.: 30 AF XY: 0.00454 AC XY: 3302 AN XY: 727028

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00467

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.00879

Gnomad4 NFE exome AF: 0.000324

Gnomad4 OTH exome AF: 0.00861

GnomAD4 genome AF: 0.00604 AC: 919 AN: 152226 Hom.: 48 Cov.: 31 AF XY: 0.00661 AC XY: 492 AN XY: 74418

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00131 Hom.: 2

Bravo AF: 0.00666

Asia WGS AF: 0.0410 AC: 144 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -

Short stature-pituitary and cerebellar defects-small sella turcica syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.57
Cadd	Benign	13
Dann	Benign	0.76

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

Other links and lift over

dbSNP: rs75857235; hg19: chr1-180199727; COSMIC: COSV55378879;