1-180249307-A-T

Variant names:

• chr1-180249307-A-T
• rs4652492
• NM_033343.4:c.248+851A>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.248+851A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: LHX4 NM_033343.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 4 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX4	NM_033343.4	c.248+851A>T		intron_variant	Intron 2 of 5	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.65+851A>T		intron_variant	Intron 2 of 5		XP_011508407.1
LHX4	XM_011510106.4	c.65+851A>T		intron_variant	Intron 2 of 5		XP_011508408.1
LHX4	XM_011510108.3	c.-29+851A>T		intron_variant	Intron 1 of 5		XP_011508410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4	c.248+851A>T		intron_variant	Intron 2 of 5	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000561113.1	n.184+838A>T		intron_variant	Intron 1 of 3	2		ENSP00000452783.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 33440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.2
DANN	Benign	0.76
PhyloP100		1.3

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: rs4652492; hg19: chr1-180218442;