chr19-49016261-G-T

Position:

• chr19-49016261-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000894.3(LHB):​c.233C>A​(p.Thr78Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,612,304 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (32 hom.)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.38

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078006387).
• BP6: Variant 19-49016261-G-T is Benign according to our data. Variant chr19-49016261-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 769028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1966/152312) while in subpopulation AFR AF= 0.0433 (1798/41570). AF 95% confidence interval is 0.0416. There are 44 homozygotes in gnomad4. There are 927 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHB	NM_000894.3	c.233C>A	p.Thr78Asn	missense_variant	3/3	ENST00000649238.3
LHB	XM_047438832.1	c.281C>A	p.Thr94Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHB	ENST00000649238.3	c.233C>A	p.Thr78Asn	missense_variant	3/3		NM_000894.3	P1
LHB	ENST00000649284.1	n.324C>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1961 AN: 152194 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00404 AC: 1012 AN: 250542 Hom.: 19 AF XY: 0.00299 AC XY: 405 AN XY: 135620

Gnomad AFR exome AF: 0.0441

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00452

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00436

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00152 AC: 2212 AN: 1459992 Hom.: 32 Cov.: 65 AF XY: 0.00126 AC XY: 915 AN XY: 726332

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00209

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00383

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.00307

GnomAD4 genome AF: 0.0129 AC: 1966 AN: 152312 Hom.: 44 Cov.: 33 AF XY: 0.0124 AC XY: 927 AN XY: 74474

Gnomad4 AFR AF: 0.0433

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00352 Hom.: 2

Bravo AF: 0.0146

ESP6500AA AF: 0.0411 AC: 181

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00442 AC: 537

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely 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	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2021	- -

Isolated lutropin deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.5
DANN	Benign	0.66
DEOGEN2	Pathogenic	0.80	D;D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.67	.;T
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.77	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.31
Sift	Benign	0.22	T;.
Sift4G	Benign	0.21	T;.
Polyphen		0.0030	B;B
Vest4		0.25
MVP		0.59
MPC		0.086
ClinPred		0.029	T
GERP RS		1.4
Varity_R		0.40
gMVP		0.35

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: rs116437960; hg19: chr19-49519518; COSMIC: COSV55486089; COSMIC: COSV55486089;