19-49016209-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000894.3(LHB):c.285T>C(p.Gly95=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,612,380 control chromosomes in the GnomAD database, including 302,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32010 hom., cov: 33)
  • Exomes 𝑓: 0.61 (270144 hom.)
• Consequence: LHB NM_000894.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.15

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-49016209-A-G is Benign according to our data. Variant chr19-49016209-A-G is described in ClinVar as [Benign]. Clinvar id is 1258177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49016209-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHB	NM_000894.3	c.285T>C	p.Gly95=	synonymous_variant	3/3	ENST00000649238.3
LHB	XM_047438832.1	c.333T>C	p.Gly111=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHB	ENST00000649238.3	c.285T>C	p.Gly95=	synonymous_variant	3/3		NM_000894.3	P1
LHB	ENST00000649284.1	n.376T>C		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97821 AN: 152010 Hom.: 31980 Cov.: 33

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.621

GnomAD3 exomes AF: 0.610 AC: 153036 AN: 251046 Hom.: 47984 AF XY: 0.602 AC XY: 81768 AN XY: 135798

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.726

Gnomad ASJ exome AF: 0.583

Gnomad EAS exome AF: 0.325

Gnomad SAS exome AF: 0.554

Gnomad FIN exome AF: 0.634

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.605 AC: 883643 AN: 1460250 Hom.: 270144 Cov.: 109 AF XY: 0.603 AC XY: 438160 AN XY: 726436

Gnomad4 AFR exome AF: 0.738

Gnomad4 AMR exome AF: 0.721

Gnomad4 ASJ exome AF: 0.587

Gnomad4 EAS exome AF: 0.342

Gnomad4 SAS exome AF: 0.555

Gnomad4 FIN exome AF: 0.636

Gnomad4 NFE exome AF: 0.609

Gnomad4 OTH exome AF: 0.605

GnomAD4 genome AF: 0.644 AC: 97897 AN: 152130 Hom.: 32010 Cov.: 33 AF XY: 0.642 AC XY: 47772 AN XY: 74374

Gnomad4 AFR AF: 0.725

Gnomad4 AMR AF: 0.698

Gnomad4 ASJ AF: 0.577

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.551

Gnomad4 FIN AF: 0.627

Gnomad4 NFE AF: 0.618

Gnomad4 OTH AF: 0.618

Alfa AF: 0.621 Hom.: 37342

Bravo AF: 0.647

Asia WGS AF: 0.451 AC: 1573 AN: 3478

EpiCase AF: 0.620

EpiControl AF: 0.618

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Isolated lutropin deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.012
Dann	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs1056917; hg19: chr19-49519466; COSMIC: COSV55485519; COSMIC: COSV55485519;