19-49016598-T-G

Variant names:

• chr19-49016598-T-G
• rs1056914
• NM_000894.3:c.132A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000649238.3(LHB):​c.132A>C​(p.Pro44Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,597,094 control chromosomes in the GnomAD database, including 211,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23023 hom., cov: 28)
  • Exomes 𝑓: 0.50 (188514 hom.)
• Consequence: LHB ENST00000649238.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.17
• Publications: 10 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=-1.03).
• BP6: Variant 19-49016598-T-G is Benign according to our data. Variant chr19-49016598-T-G is described in ClinVar as Benign. ClinVar VariationId is 518302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649238.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	NM_000894.3	MANE Select	c.132A>C	p.Pro44Pro	synonymous	Exon 2 of 3	NP_000885.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	ENST00000649238.3	MANE Select	c.132A>C	p.Pro44Pro	synonymous	Exon 2 of 3	ENSP00000497294.2
	LHB	ENST00000649284.1		n.223A>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.546 AC: 81979 AN: 150144 Hom.: 23001 Cov.: 28

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.510

GnomAD2 exomes AF: 0.518 AC: 128825 AN: 248844 AF XY: 0.511

Gnomad AFR exome AF: 0.665

Gnomad AMR exome AF: 0.663

Gnomad ASJ exome AF: 0.508

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.505

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.504 AC: 729762 AN: 1446832 Hom.: 188514 Cov.: 95 AF XY: 0.503 AC XY: 362326 AN XY: 720008

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.670 AC: 22296 AN: 33276

American (AMR) AF: 0.655 AC: 28891 AN: 44102

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 13205 AN: 25900

East Asian (EAS) AF: 0.285 AC: 11273 AN: 39546

South Asian (SAS) AF: 0.505 AC: 43168 AN: 85504

European-Finnish (FIN) AF: 0.489 AC: 25562 AN: 52270

Middle Eastern (MID) AF: 0.531 AC: 2383 AN: 4488

European-Non Finnish (NFE) AF: 0.502 AC: 552673 AN: 1101906

Other (OTH) AF: 0.507 AC: 30311 AN: 59840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.546 AC: 82032 AN: 150262 Hom.: 23023 Cov.: 28 AF XY: 0.545 AC XY: 39925 AN XY: 73290

African (AFR) AF: 0.655 AC: 26709 AN: 40764

American (AMR) AF: 0.598 AC: 9035 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1702 AN: 3452

East Asian (EAS) AF: 0.271 AC: 1381 AN: 5092

South Asian (SAS) AF: 0.503 AC: 2402 AN: 4774

European-Finnish (FIN) AF: 0.476 AC: 4927 AN: 10352

Middle Eastern (MID) AF: 0.538 AC: 157 AN: 292

European-Non Finnish (NFE) AF: 0.507 AC: 34172 AN: 67428

Other (OTH) AF: 0.505 AC: 1058 AN: 2094

Alfa AF: 0.484 Hom.: 5017

Bravo AF: 0.556

EpiCase AF: 0.515

EpiControl AF: 0.506

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Isolated lutropin deficiency (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.016
DANN	Benign	0.32
PhyloP100		-5.2
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1056914; hg19: chr19-49519855; COSMIC: COSV55484209; COSMIC: COSV55484209;