chr19-49016294-G-C

Position:

• chr19-49016294-G-C

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.200C>G​(p.Ala67Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,611,276 control chromosomes in the GnomAD database, including 80 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 0.013 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (46 hom.)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.406

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=0.0023105145).
• BP6: Variant 19-49016294-G-C is Benign according to our data. Variant chr19-49016294-G-C is described in ClinVar as [Benign]. Clinvar id is 781469.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 = 0.0127 (1939/152300) while in subpopulation AFR AF= 0.0441 (1834/41568). AF 95% confidence interval is 0.0424. There are 34 homozygotes in gnomad4. There are 910 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHB	NM_000894.3	c.200C>G	p.Ala67Gly	missense_variant	3/3	ENST00000649238.3
LHB	XM_047438832.1	c.248C>G	p.Ala83Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHB	ENST00000649238.3	c.200C>G	p.Ala67Gly	missense_variant	3/3		NM_000894.3	P1
LHB	ENST00000649284.1	n.291C>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1932 AN: 152182 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00326 AC: 812 AN: 249432 Hom.: 28 AF XY: 0.00232 AC XY: 313 AN XY: 135184

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00127 AC: 1855 AN: 1458976 Hom.: 46 Cov.: 62 AF XY: 0.00106 AC XY: 768 AN XY: 725878

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.0127 AC: 1939 AN: 152300 Hom.: 34 Cov.: 32 AF XY: 0.0122 AC XY: 910 AN XY: 74462

Gnomad4 AFR AF: 0.0441

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.0145

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00409 AC: 496

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.3
DANN	Benign	0.83
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.17
Sift	Benign	0.26	T;.
Sift4G	Benign	0.44	T;.
Polyphen		0.0010	B;B
Vest4		0.17
MVP		0.72
MPC		0.077
ClinPred		0.0082	T
GERP RS		2.0
Varity_R		0.076
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs73942398; hg19: chr19-49519551;