NM_000894.3:c.373G>A

Variant names:

• chr19-49016121-C-T
• rs867597840
• NM_000894.3:c.373G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000894.3(LHB):​c.373G>A​(p.Asp125Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.921

Genes affected

LHB (HGNC:6584): (luteinizing hormone subunit beta) This gene is a member of the glycoprotein hormone beta chain family and encodes the beta subunit of luteinizing hormone (LH). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and an unique beta subunit which confers biological specificity. LH is expressed in the pituitary gland and promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids. The genes for the beta chains of chorionic gonadotropin and for luteinizing hormone are contiguous on chromosome 19q13.3. Mutations in this gene are associated with hypogonadism which is characterized by infertility and pseudohermaphroditism. [provided by RefSeq, Jul 2008]

RUVBL2 (HGNC:10475): (RuvB like AAA ATPase 2) This gene encodes the second human homologue of the bacterial RuvB gene. Bacterial RuvB protein is a DNA helicase essential for homologous recombination and DNA double-strand break repair. Functional analysis showed that this gene product has both ATPase and DNA helicase activities. This gene is physically linked to the CGB/LHB gene cluster on chromosome 19q13.3, and is very close (55 nt) to the LHB gene, in the opposite orientation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2808112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHB	NM_000894.3	c.373G>A	p.Asp125Asn	missense_variant	Exon 3 of 3	ENST00000649238.3	NP_000885.1
RUVBL2	NM_006666.3	c.*279C>T		downstream_gene_variant		ENST00000595090.6	NP_006657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHB	ENST00000649238.3	c.373G>A	p.Asp125Asn	missense_variant	Exon 3 of 3		NM_000894.3	ENSP00000497294.2
RUVBL2	ENST00000595090.6	c.*279C>T		downstream_gene_variant		1	NM_006666.3	ENSP00000473172.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373G>A (p.D125N) alteration is located in exon 3 (coding exon 3) of the LHB gene. This alteration results from a G to A substitution at nucleotide position 373, causing the aspartic acid (D) at amino acid position 125 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.24	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.19	N;.
REVEL	Benign	0.13
Sift	Benign	0.29	T;.
Sift4G	Benign	0.49	T;.
Polyphen		1.0	D;D
Vest4		0.11
MutPred		0.36		Gain of catalytic residue at D125 (P = 0.0747);Gain of catalytic residue at D125 (P = 0.0747);
MVP		0.71
MPC		0.075
ClinPred		0.68	D
GERP RS		0.73
Varity_R		0.065
gMVP		0.15

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: rs867597840; hg19: chr19-49519378; COSMIC: COSV99669316; COSMIC: COSV99669316;