rs17300107

Variant names:

• chr1-180265960-C-T
• rs17300107
• NM_033343.4:c.249-432C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033343.4(LHX4):​c.249-432C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 152,192 control chromosomes in the GnomAD database, including 2,012 homozygotes. 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: 𝑓 0.15 (2012 hom., cov: 32)
• Consequence: LHX4 NM_033343.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.00
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX4	NM_033343.4	c.249-432C>T		intron_variant	Intron 2 of 5	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.66-432C>T		intron_variant	Intron 2 of 5		XP_011508407.1
LHX4	XM_011510106.4	c.66-432C>T		intron_variant	Intron 2 of 5		XP_011508408.1
LHX4	XM_011510108.3	c.-28-243C>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.249-432C>T		intron_variant	Intron 2 of 5	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000561113.1	n.185-432C>T		intron_variant	Intron 1 of 3	2		ENSP00000452783.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22576 AN: 152074 Hom.: 2014 Cov.: 32

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.148 AC: 22568 AN: 152192 Hom.: 2012 Cov.: 32 AF XY: 0.147 AC XY: 10924 AN XY: 74412

African (AFR) AF: 0.0515 AC: 2140 AN: 41548

American (AMR) AF: 0.144 AC: 2199 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 743 AN: 3470

East Asian (EAS) AF: 0.0321 AC: 166 AN: 5172

South Asian (SAS) AF: 0.185 AC: 889 AN: 4816

European-Finnish (FIN) AF: 0.161 AC: 1708 AN: 10590

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14150 AN: 67984

Other (OTH) AF: 0.164 AC: 346 AN: 2114

Alfa AF: 0.170 Hom.: 2102

Bravo AF: 0.140

Asia WGS AF: 0.110 AC: 381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.013
DANN	Benign	0.79
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs17300107; hg19: chr1-180235095;