NM_000894.3:c.189C>G

Variant names:

• chr19-49016305-G-C
• rs149516688
• NM_000894.3:c.189C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000894.3(LHB):​c.189C>G​(p.Arg63Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,610,844 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R63R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: LHB NM_000894.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.101
• Publications: 1 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]

LHB Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 23 with or without anosmia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-49016305-G-C is Benign according to our data. Variant chr19-49016305-G-C is described in ClinVar as Benign. ClinVar VariationId is 714891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.101 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00481 (732/152300) while in subpopulation AFR AF = 0.0166 (691/41566). AF 95% confidence interval is 0.0156. There are 4 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.189C>G	p.Arg63Arg	synonymous	Exon 3 of 3	NP_000885.1	P01229

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	ENST00000649238.3	MANE Select	c.189C>G	p.Arg63Arg	synonymous	Exon 3 of 3	ENSP00000497294.2	P01229
	LHB	ENST00000649284.1		n.280C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152184 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00135 AC: 336 AN: 249040 AF XY: 0.00105

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000543 AC: 792 AN: 1458544 Hom.: 7 Cov.: 64 AF XY: 0.000462 AC XY: 335 AN XY: 725700

African (AFR) AF: 0.0186 AC: 620 AN: 33412

American (AMR) AF: 0.00103 AC: 46 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52148

Middle Eastern (MID) AF: 0.000229 AC: 1 AN: 4376

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111746

Other (OTH) AF: 0.00110 AC: 66 AN: 60212

GnomAD4 genome AF: 0.00481 AC: 732 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74464

African (AFR) AF: 0.0166 AC: 691 AN: 41566

American (AMR) AF: 0.00170 AC: 26 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.00579

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.21
DANN	Benign	0.69
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149516688; hg19: chr19-49519562;