rs3845395

Variant names:

• chr1-180244132-G-C
• rs3845395
• NM_033343.4:c.77-4153G>C

Variant summary

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

The NM_033343.4(LHX4):​c.77-4153G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,200 control chromosomes in the GnomAD database, including 5,519 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 0.24 (5519 hom., cov: 32)
• Consequence: LHX4 NM_033343.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.605
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX4	NM_033343.4	c.77-4153G>C		intron_variant	Intron 1 of 5	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.-107-4153G>C		intron_variant	Intron 1 of 5		XP_011508407.1
LHX4	XM_011510106.4	c.-107-4153G>C		intron_variant	Intron 1 of 5		XP_011508408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4	c.77-4153G>C		intron_variant	Intron 1 of 5	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000558139.1	n.309-4153G>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36437 AN: 152082 Hom.: 5522 Cov.: 32

Gnomad AFR AF: 0.0554

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.239 AC: 36424 AN: 152200 Hom.: 5519 Cov.: 32 AF XY: 0.241 AC XY: 17950 AN XY: 74390

African (AFR) AF: 0.0552 AC: 2296 AN: 41558

American (AMR) AF: 0.311 AC: 4763 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 971 AN: 3468

East Asian (EAS) AF: 0.380 AC: 1971 AN: 5184

South Asian (SAS) AF: 0.210 AC: 1014 AN: 4824

European-Finnish (FIN) AF: 0.357 AC: 3764 AN: 10558

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20805 AN: 67988

Other (OTH) AF: 0.226 AC: 479 AN: 2116

Alfa AF: 0.274 Hom.: 883

Bravo AF: 0.229

Asia WGS AF: 0.253 AC: 881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.45
DANN	Benign	0.55
PhyloP100		-0.60
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: rs3845395; hg19: chr1-180213267;