rs146251380

Variant names:

• chr19-49016232-G-A
• rs146251380
• NM_000894.3:c.262C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49016232-G-A
• chr19-49016232-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000894.3(LHB):​c.262C>T​(p.Arg88Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,612,492 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.61
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023076266).
• BP6: Variant 19-49016232-G-A is Benign according to our data. Variant chr19-49016232-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 721564.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00021 (32/152318) while in subpopulation EAS AF = 0.00521 (27/5178). AF 95% confidence interval is 0.00368. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.262C>T	p.Arg88Trp	missense	Exon 3 of 3	NP_000885.1	P01229
	RUVBL2	NM_001321191.1		c.*390G>A		downstream_gene	N/A	NP_001308120.1	Q9Y230-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	ENST00000649238.3	MANE Select	c.262C>T	p.Arg88Trp	missense	Exon 3 of 3	ENSP00000497294.2	P01229
	LHB	ENST00000649284.1		n.353C>T		non_coding_transcript_exon	Exon 2 of 2
	RUVBL2	ENST00000888165.1		c.*390G>A		downstream_gene	N/A	ENSP00000558224.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000399 AC: 100 AN: 250908 AF XY: 0.000324

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00495

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1460174 Hom.: 0 Cov.: 66 AF XY: 0.000171 AC XY: 124 AN XY: 726420

African (AFR) AF: 0.0000299 AC: 1 AN: 33430

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00315 AC: 125 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4556

European-Non Finnish (NFE) AF: 0.0000773 AC: 86 AN: 1111888

Other (OTH) AF: 0.000133 AC: 8 AN: 60264

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000340

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.057	B
Vest4		0.26
MVP		0.88
MPC		0.086
ClinPred		0.092	T
GERP RS		3.7
Varity_R		0.57
gMVP		0.41
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146251380; hg19: chr19-49519489;