chr1-180230396-G-T

Variant names:

• chr1-180230396-G-T
• rs565557892
• NM_033343.4:c.-134G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033343.4(LHX4):​c.-134G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 604,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: LHX4 NM_033343.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• short stature-pituitary and cerebellar defects-small sella turcica syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	NM_033343.4	MANE Select	c.-134G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_203129.1	A0A0S2Z5S4
	LHX4	NM_033343.4	MANE Select	c.-134G>T		5_prime_UTR	Exon 1 of 6	NP_203129.1	A0A0S2Z5S4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.-134G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000263726.2	Q969G2
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.-134G>T		5_prime_UTR	Exon 1 of 6	ENSP00000263726.2	Q969G2
	LHX4	ENST00000930099.1		c.-134G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000600158.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000165 AC: 1 AN: 604760 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 322748

African (AFR) AF: 0.00 AC: 0 AN: 16606

American (AMR) AF: 0.00 AC: 0 AN: 34144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19760

East Asian (EAS) AF: 0.00 AC: 0 AN: 32072

South Asian (SAS) AF: 0.00 AC: 0 AN: 62158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2764

European-Non Finnish (NFE) AF: 0.00000269 AC: 1 AN: 371062

Other (OTH) AF: 0.00 AC: 0 AN: 31928

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		1.1
PromoterAI		-0.036	Neutral

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

Other links and lift over

dbSNP: rs565557892; hg19: chr1-180199531;