rs587776662

Positions:

• chr1-180266430-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_033343.4(LHX4):​c.293dupC​(p.Thr99fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHX4 NM_033343.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.28

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-180266430-T-TC is Pathogenic according to our data. Variant chr1-180266430-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 18444.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX4	NM_033343.4	c.293dupC	p.Thr99fs	frameshift_variant	3/6	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.110dupC	p.Thr38fs	frameshift_variant	3/6		XP_011508407.1
LHX4	XM_011510106.4	c.110dupC	p.Thr38fs	frameshift_variant	3/6		XP_011508408.1
LHX4	XM_011510108.3	c.68dupC	p.Thr24fs	frameshift_variant	3/6		XP_011508410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4	c.293dupC	p.Thr99fs	frameshift_variant	3/6	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000561113.1	n.229dupC		non_coding_transcript_exon_variant	2/4	2		ENSP00000452783.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587776662; hg19: chr1-180235565;