1-180271530-T-C

Position:

• chr1-180271530-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_033343.4(LHX4):​c.602T>C​(p.Val201Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHX4 NM_033343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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-AS1 (HGNC:):

ACBD6 (HGNC:23339): (acyl-CoA binding domain containing 6) Predicted to enable fatty-acyl-CoA binding activity and lipid binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity LHX4_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_033343.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX4	NM_033343.4	c.602T>C	p.Val201Ala	missense_variant	4/6	ENST00000263726.4
LHX4-AS1	NR_037642.1	n.790A>G		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX4	ENST00000263726.4	c.602T>C	p.Val201Ala	missense_variant	4/6	1	NM_033343.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 05, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.68		Gain of disorder (P = 0.0783);
MVP		0.98
MPC		0.38
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.82
gMVP		0.70

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: rs1648658489; hg19: chr1-180240665;