rs16855642

chr1-180266593-C-Gchr1-180266593-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 2/2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX4	NM_033343.4	c.450C>G	p.Asn150Lys	missense_variant, splice_region_variant	3/6	ENST00000263726.4
LHX4	XM_011510105.3	c.267C>G	p.Asn89Lys	missense_variant, splice_region_variant	3/6
LHX4	XM_011510106.4	c.267C>G	p.Asn89Lys	missense_variant, splice_region_variant	3/6
LHX4	XM_011510108.3	c.225C>G	p.Asn75Lys	missense_variant, splice_region_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX4	ENST00000263726.4	c.450C>G	p.Asn150Lys	missense_variant, splice_region_variant	3/6	1	NM_033343.4	P1
LHX4	ENST00000561113.1	c.389C>G	p.Thr130Arg	missense_variant, splice_region_variant, NMD_transcript_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250414 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135440

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 SAS exome AF: 0.0000327

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: 1 AN: 1461628 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	12
Dann	Benign	0.73
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	-0.65	N
MutationTaster	Benign	0.000016	P
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	1.7	N
REVEL	Uncertain	0.40
Sift	Benign	0.77	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.56
MutPred		0.38		Gain of ubiquitination at N150 (P = 7e-04);
MVP		0.81
MPC		0.33
ClinPred		0.031	T
GERP RS		-2.1
Varity_R		0.14
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs16855642; hg19: chr1-180235728;