rs16855642

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033343.4(LHX4):c.450C>G(p.Asn150Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N150N) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LHX4
NM_033343.4 missense, splice_region

Scores

Splicing: ADA: 0.0003636

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.769

Publications

12 publications found

Variant links:

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

LHX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX4	NM_033343.4 link	c.450C>G	p.Asn150Lys	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000263726.4	NP_203129.1	Q969G2A0A0S2Z5S4
LHX4	XM_011510105.3 link	c.267C>G	p.Asn89Lys	missense_variant, splice_region_variant	Exon 3 of 6		XP_011508407.1
LHX4	XM_011510106.4 link	c.267C>G	p.Asn89Lys	missense_variant, splice_region_variant	Exon 3 of 6		XP_011508408.1
LHX4	XM_011510108.3 link	c.225C>G	p.Asn75Lys	missense_variant, splice_region_variant	Exon 3 of 6		XP_011508410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4 link	c.450C>G	p.Asn150Lys	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_033343.4	ENSP00000263726.2		Q969G2
LHX4	ENST00000561113.1 link	n.386C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000452783.1		H0YKF4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250414

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461628

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111840

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.074

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.47

MutationAssessor

Benign

-0.65

PhyloP100

-0.77

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

1.7

REVEL

Uncertain

0.40

Sift

Benign

0.77

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.56

MutPred

0.38

Gain of ubiquitination at N150 (P = 7e-04);

MVP

0.81

MPC

0.33

ClinPred

0.031

GERP RS

-2.1

Varity_R

0.14

gMVP

0.37

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00036

dbscSNV1_RF

Benign

0.034

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

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rs16855642

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over