NM_000894.3:c.104T>C

Variant names:

• chr19-49016626-A-G
• rs34349826
• NM_000894.3:c.104T>C

Variant summary

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

The NM_000894.3(LHB):​c.104T>C​(p.Ile35Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 1,593,286 control chromosomes in the GnomAD database, including 5,079 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (479 hom., cov: 31)
  • Exomes 𝑓: 0.071 (4600 hom.)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.25

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=0.0055906475).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHB	NM_000894.3	c.104T>C	p.Ile35Thr	missense_variant	Exon 2 of 3	ENST00000649238.3	NP_000885.1
LHB	XM_047438832.1	c.152T>C	p.Ile51Thr	missense_variant	Exon 1 of 2		XP_047294788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHB	ENST00000649238.3	c.104T>C	p.Ile35Thr	missense_variant	Exon 2 of 3		NM_000894.3	ENSP00000497294.2
LHB	ENST00000649284.1	n.195T>C		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0746 AC: 11242 AN: 150796 Hom.: 476 Cov.: 31

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0827

Gnomad OTH AF: 0.0806

GnomAD3 exomes AF: 0.0487 AC: 11597 AN: 238330 Hom.: 640 AF XY: 0.0471 AC XY: 6066 AN XY: 128818

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.0351

Gnomad ASJ exome AF: 0.0396

Gnomad EAS exome AF: 0.0458

Gnomad SAS exome AF: 0.0205

Gnomad FIN exome AF: 0.0777

Gnomad NFE exome AF: 0.0576

Gnomad OTH exome AF: 0.0561

GnomAD4 exome AF: 0.0710 AC: 102352 AN: 1442378 Hom.: 4600 Cov.: 132 AF XY: 0.0703 AC XY: 50450 AN XY: 717722

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.0567

Gnomad4 EAS exome AF: 0.0536

Gnomad4 SAS exome AF: 0.0262

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.0745

Gnomad4 OTH exome AF: 0.0714

GnomAD4 genome AF: 0.0746 AC: 11260 AN: 150908 Hom.: 479 Cov.: 31 AF XY: 0.0744 AC XY: 5484 AN XY: 73726

Gnomad4 AFR AF: 0.0570

Gnomad4 AMR AF: 0.0670

Gnomad4 ASJ AF: 0.0645

Gnomad4 EAS AF: 0.0525

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.0826

Gnomad4 OTH AF: 0.0821

Alfa AF: 0.0690 Hom.: 136

TwinsUK AF: 0.0631 AC: 234

ALSPAC AF: 0.0734 AC: 283

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.0337 AC: 290

ExAC AF: 0.0683 AC: 8297

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 7904610, 23725475, 22108961, 7714098, 19890021, 25111116, 7586598) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	10
DANN	Benign	0.52
DEOGEN2	Benign	0.42	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.58	.;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-2.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	4.5	N;.
REVEL	Benign	0.24
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;B
Vest4		0.048
MPC		0.094
ClinPred		0.0024	T
GERP RS		3.1
Varity_R		0.036
gMVP		0.33

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: rs34349826; hg19: chr19-49519883;