NM_033343.4:c.983A>T

Variant names:

• chr1-180274389-A-T
• rs7536561
• NM_033343.4:c.983A>T

Variant summary

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

The NM_033343.4(LHX4):​c.983A>T​(p.Asn328Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N328S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHX4 NM_033343.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52
• Publications: 46 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]

ACBD6 (HGNC:23339): (acyl-CoA binding domain containing 6) Predicted to enable fatty-acyl-CoA binding activity and lipid binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LHX4-AS1 (HGNC:40982): (LHX4 antisense RNA 1)

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	NM_033343.4	MANE Select	c.983A>T	p.Asn328Ile	missense	Exon 6 of 6	NP_203129.1	A0A0S2Z5S4
	LHX4-AS1	NR_037642.1		n.31+262T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.983A>T	p.Asn328Ile	missense	Exon 6 of 6	ENSP00000263726.2	Q969G2
	LHX4	ENST00000930099.1		c.968A>T	p.Asn323Ile	missense	Exon 6 of 6	ENSP00000600158.1
	ACBD6	ENST00000642319.1		c.*936+262T>A		intron	N/A	ENSP00000495710.1	Q9BR61

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.060	T
Polyphen		0.32	B
Vest4		0.50
MutPred		0.46		Loss of disorder (P = 0.0461)
MVP		0.95
MPC		0.55
ClinPred		0.85	D
GERP RS		3.3
Varity_R		0.28
gMVP		0.53
Mutation Taster		=71/29	polymorphism

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: rs7536561; hg19: chr1-180243524;