19-49016648-A-G

Position:

• chr19-49016648-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000894.3(LHB):​c.82T>C​(p.Trp28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0756 in 1,608,732 control chromosomes in the GnomAD database, including 5,114 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (484 hom., cov: 31)
  • Exomes 𝑓: 0.076 (4630 hom.)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.604

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005592197).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHB	NM_000894.3	c.82T>C	p.Trp28Arg	missense_variant	2/3	ENST00000649238.3	NP_000885.1
LHB	XM_047438832.1	c.130T>C	p.Trp44Arg	missense_variant	1/2		XP_047294788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHB	ENST00000649238.3	c.82T>C	p.Trp28Arg	missense_variant	2/3		NM_000894.3	ENSP00000497294	P1
LHB	ENST00000649284.1	n.173T>C		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11386 AN: 150980 Hom.: 481 Cov.: 31

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.0528

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.0816

GnomAD3 exomes AF: 0.0648 AC: 15994 AN: 246848 Hom.: 694 AF XY: 0.0642 AC XY: 8590 AN XY: 133756

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0551

Gnomad EAS exome AF: 0.0585

Gnomad SAS exome AF: 0.0277

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0783

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0757 AC: 110271 AN: 1457636 Hom.: 4630 Cov.: 135 AF XY: 0.0750 AC XY: 54362 AN XY: 725230

Gnomad4 AFR exome AF: 0.0584

Gnomad4 AMR exome AF: 0.0449

Gnomad4 ASJ exome AF: 0.0605

Gnomad4 EAS exome AF: 0.0564

Gnomad4 SAS exome AF: 0.0280

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.0795

Gnomad4 OTH exome AF: 0.0754

GnomAD4 genome AF: 0.0755 AC: 11406 AN: 151096 Hom.: 484 Cov.: 31 AF XY: 0.0753 AC XY: 5557 AN XY: 73796

Gnomad4 AFR AF: 0.0586

Gnomad4 AMR AF: 0.0675

Gnomad4 ASJ AF: 0.0652

Gnomad4 EAS AF: 0.0533

Gnomad4 SAS AF: 0.0257

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.0831

Gnomad4 OTH AF: 0.0831

Alfa AF: 0.0709 Hom.: 142

Bravo AF: 0.0726

TwinsUK AF: 0.0636 AC: 236

ALSPAC AF: 0.0734 AC: 283

ESP6500AA AF: 0.0431 AC: 190

ESP6500EA AF: 0.0747 AC: 642

ExAC AF: 0.0705 AC: 8558

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	This variant is associated with the following publications: (PMID: 7586598, 25111116, 19890021, 7714098, 22108961, 23725475, 7904610) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.0
DANN	Benign	0.56
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.061	.;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.8	N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.24	N;.
REVEL	Benign	0.17
Sift	Benign	0.39	T;.
Sift4G	Benign	0.40	T;.
Polyphen		0.0	B;B
Vest4		0.010
MutPred		0.16		Gain of disorder (P = 0.0104);Gain of disorder (P = 0.0104);
MPC		0.13
ClinPred		0.0012	T
GERP RS		0.27
Varity_R		0.066
gMVP		0.67

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: rs1800447; hg19: chr19-49519905; COSMIC: COSV55485237; COSMIC: COSV55485237;