NM_033343.4:c.91G>T

Variant names:

• chr1-180248299-G-T
• NM_033343.4:c.91G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033343.4(LHX4):​c.91G>T​(p.Ala31Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A31T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LHX4 NM_033343.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83

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 rank	MANE	Protein	UniProt
LHX4	NM_033343.4	c.91G>T	p.Ala31Ser	missense_variant	Exon 2 of 6	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.-93G>T		5_prime_UTR_variant	Exon 2 of 6		XP_011508407.1
LHX4	XM_011510106.4	c.-93G>T		5_prime_UTR_variant	Exon 2 of 6		XP_011508408.1
LHX4	XM_011510108.3	c.-186G>T		upstream_gene_variant			XP_011508410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4	c.91G>T	p.Ala31Ser	missense_variant	Exon 2 of 6	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000558139.1	n.323G>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
LHX4	ENST00000561113.1	n.14G>T		non_coding_transcript_exon_variant	Exon 1 of 4	2		ENSP00000452783.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.0073	D
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.42
Sift	Benign	0.096	T
Sift4G	Benign	0.15	T
Polyphen		0.064	B
Vest4		0.47
MutPred		0.64		Loss of catalytic residue at A31 (P = 0.1476);
MVP		0.90
MPC		0.26
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.25

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-180217434; COSMIC: COSV55373655;