1-180230358-A-G

Position:

• chr1-180230358-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033343.4(LHX4):​c.-172A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LHX4 NM_033343.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX4	NM_033343.4	c.-172A>G		5_prime_UTR_variant	1/6	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.-108+1445A>G		intron_variant			XP_011508407.1
LHX4	XM_011510106.4	c.-108+1205A>G		intron_variant			XP_011508408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726	c.-172A>G		5_prime_UTR_variant	1/6	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000558139.1	n.61A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 40 AN: 141252 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000684

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.000429

Gnomad SAS AF: 0.000230

Gnomad FIN AF: 0.000205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000216 AC: 105 AN: 485060 Hom.: 0 Cov.: 4 AF XY: 0.000291 AC XY: 75 AN XY: 258004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000255

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000878

Gnomad4 FIN exome AF: 0.000100

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000290 AC: 41 AN: 141354 Hom.: 0 Cov.: 31 AF XY: 0.000377 AC XY: 26 AN XY: 68970

Gnomad4 AFR AF: 0.0000267

Gnomad4 AMR AF: 0.000137

Gnomad4 ASJ AF: 0.000304

Gnomad4 EAS AF: 0.000430

Gnomad4 SAS AF: 0.000230

Gnomad4 FIN AF: 0.000205

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

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

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.83

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: rs376657735; hg19: chr1-180199493; COSMIC: COSV55372507;