17-36942785-A-G

Position:

• chr17-36942785-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_005568.5(LHX1):​c.875A>G​(p.Asn292Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000359 in 1,391,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: LHX1 NM_005568.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34

Genes affected

LHX1 (HGNC:6593): (LIM homeobox 1) 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 important for the development of the renal and urogenital systems. This gene is a candidate for Mayer-Rokitansky-Kuster-Hauser syndrome, a disorder characterized by anomalies in the female genital tract. [provided by RefSeq, Dec 2010]

ENSG00000276707 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36105597).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX1	NM_005568.5	c.875A>G	p.Asn292Ser	missense_variant	5/5	ENST00000614239.1	NP_005559.2
LHX1	XM_047435966.1	c.875A>G	p.Asn292Ser	missense_variant	6/6		XP_047291922.1
LHX1	XM_047435967.1	c.875A>G	p.Asn292Ser	missense_variant	6/6		XP_047291923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX1	ENST00000614239.1	c.875A>G	p.Asn292Ser	missense_variant	5/5	1	NM_005568.5	ENSP00000477829.1
LHX1	ENST00000621767.1	c.67+420A>G		intron_variant		2		ENSP00000481496.1
ENSG00000276707	ENST00000614759.1	n.367+305T>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1391802 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 683496

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000466

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.875A>G (p.N292S) alteration is located in exon 5 (coding exon 5) of the LHX1 gene. This alteration results from a A to G substitution at nucleotide position 875, causing the asparagine (N) at amino acid position 292 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.75	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.41
MutPred		0.33		Gain of phosphorylation at N292 (P = 0.0341);
MVP		0.40
ClinPred		0.73	D
GERP RS		4.1
Varity_R		0.36
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs2070774388; hg19: chr17-35300082;