chr19-49016616-G-C

Variant names:

• chr19-49016616-G-C
• rs6521
• NM_000894.3:c.114C>G

Variant summary

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

The NM_000894.3(LHB):​c.114C>G​(p.Val38Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,587,092 control chromosomes in the GnomAD database, including 258,586 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. V38V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.55 (22978 hom., cov: 28)
  • Exomes 𝑓: 0.57 (235608 hom.)
• Consequence: LHB NM_000894.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -8.53
• Publications: 14 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=-0.89).
• BP6: Variant 19-49016616-G-C is Benign according to our data. Variant chr19-49016616-G-C is described in ClinVar as Benign. ClinVar VariationId is 518303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

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.114C>G	p.Val38Val	synonymous	Exon 2 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.114C>G	p.Val38Val	synonymous	Exon 2 of 3	ENSP00000497294.2	P01229
	LHB	ENST00000649284.1		n.205C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.547 AC: 82086 AN: 150118 Hom.: 22960 Cov.: 28

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.530

GnomAD2 exomes AF: 0.562 AC: 136387 AN: 242482 AF XY: 0.559

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.318

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.566 AC: 813670 AN: 1436860 Hom.: 235608 Cov.: 110 AF XY: 0.565 AC XY: 404184 AN XY: 715066

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

African (AFR) AF: 0.475 AC: 15683 AN: 32994

American (AMR) AF: 0.675 AC: 29929 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 13653 AN: 25778

East Asian (EAS) AF: 0.341 AC: 13409 AN: 39348

South Asian (SAS) AF: 0.522 AC: 44751 AN: 85726

European-Finnish (FIN) AF: 0.628 AC: 32278 AN: 51438

Middle Eastern (MID) AF: 0.575 AC: 2607 AN: 4534

European-Non Finnish (NFE) AF: 0.575 AC: 628394 AN: 1093160

Other (OTH) AF: 0.554 AC: 32966 AN: 59512

⚠️ 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: 0.547 AC: 82145 AN: 150232 Hom.: 22978 Cov.: 28 AF XY: 0.547 AC XY: 40126 AN XY: 73298

African (AFR) AF: 0.472 AC: 19228 AN: 40752

American (AMR) AF: 0.629 AC: 9518 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1770 AN: 3456

East Asian (EAS) AF: 0.324 AC: 1651 AN: 5088

South Asian (SAS) AF: 0.521 AC: 2492 AN: 4786

European-Finnish (FIN) AF: 0.614 AC: 6355 AN: 10350

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.583 AC: 39270 AN: 67388

Other (OTH) AF: 0.527 AC: 1100 AN: 2086

Alfa AF: 0.539 Hom.: 6181

Bravo AF: 0.540

ClinVar

ClinVar submissions

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	-0.89
CADD	Benign	0.018
DANN	Benign	0.69
PhyloP100		-8.5
PromoterAI		-0.030	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: rs6521; hg19: chr19-49519873; COSMIC: COSV55484075; COSMIC: COSV55484075;