chr19-49016121-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000894.3(LHB):​c.373G>T​(p.Asp125Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. D125N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.921
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4078666).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000894.3. 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
	LHB	NM_000894.3	MANE Select	c.373G>T	p.Asp125Tyr	missense	Exon 3 of 3	NP_000885.1	P01229
	RUVBL2	NM_006666.3	MANE Select	c.*279C>A		downstream_gene	N/A	NP_006657.1	Q9Y230-1
	RUVBL2	NM_001321190.2		c.*279C>A		downstream_gene	N/A	NP_001308119.1	B3KNL2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	ENST00000649238.3	MANE Select	c.373G>T	p.Asp125Tyr	missense	Exon 3 of 3	ENSP00000497294.2	P01229
	LHB	ENST00000649284.1		n.464G>T		non_coding_transcript_exon	Exon 2 of 2
	RUVBL2	ENST00000595090.6	TSL:1 MANE Select	c.*279C>A		downstream_gene	N/A	ENSP00000473172.1	Q9Y230-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251360 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460648 Hom.: 0 Cov.: 88 AF XY: 0.00 AC XY: 0 AN XY: 726640

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.92
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.21
Sift	Benign	0.082	T
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.37		Loss of disorder (P = 0.0405)
MVP		0.75
MPC		0.46
ClinPred		0.58	D
GERP RS		0.73
Varity_R		0.047
gMVP		0.33
Mutation Taster		=98/2	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: rs867597840; hg19: chr19-49519378;