XM_047438832.1:c.-338T>A

Variant names:

• chr19-49017115-A-T
• rs3752210
• XM_047438832.1:c.-338T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The XM_047438832.1(LHB):​c.-338T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,654 control chromosomes in the GnomAD database, including 291,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36518 hom., cov: 33)
  • Exomes 𝑓: 0.59 (254864 hom.)
• Consequence: LHB XM_047438832.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.62
• Publications: 11 publications found

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]

LHB Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 23 with or without anosmia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-49017115-A-T is Benign according to our data. Variant chr19-49017115-A-T is described in ClinVar as Benign. ClinVar VariationId is 1292721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHB	XM_047438832.1	c.-338T>A		5_prime_UTR_variant	Exon 1 of 2		XP_047294788.1
LHB	NM_000894.3	c.-34T>A		upstream_gene_variant		ENST00000649238.3	NP_000885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHB	ENST00000649238.3	c.-34T>A		upstream_gene_variant			NM_000894.3	ENSP00000497294.2

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102838 AN: 151992 Hom.: 36470 Cov.: 33

Gnomad AFR AF: 0.894

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.694

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.604 AC: 151658 AN: 251234 AF XY: 0.592

Gnomad AFR exome AF: 0.902

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.566

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.592

GnomAD4 exome AF: 0.586 AC: 855891 AN: 1461542 Hom.: 254864 Cov.: 62 AF XY: 0.583 AC XY: 423914 AN XY: 727088

African (AFR) AF: 0.909 AC: 30418 AN: 33470

American (AMR) AF: 0.711 AC: 31811 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 14909 AN: 26128

East Asian (EAS) AF: 0.342 AC: 13596 AN: 39700

South Asian (SAS) AF: 0.533 AC: 46012 AN: 86248

European-Finnish (FIN) AF: 0.629 AC: 33595 AN: 53410

Middle Eastern (MID) AF: 0.653 AC: 3752 AN: 5750

European-Non Finnish (NFE) AF: 0.581 AC: 645907 AN: 1111760

Other (OTH) AF: 0.595 AC: 35891 AN: 60366

GnomAD4 genome AF: 0.677 AC: 102938 AN: 152112 Hom.: 36518 Cov.: 33 AF XY: 0.674 AC XY: 50104 AN XY: 74354

African (AFR) AF: 0.894 AC: 37125 AN: 41538

American (AMR) AF: 0.694 AC: 10607 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3470

East Asian (EAS) AF: 0.332 AC: 1710 AN: 5148

South Asian (SAS) AF: 0.532 AC: 2568 AN: 4824

European-Finnish (FIN) AF: 0.620 AC: 6554 AN: 10566

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40304 AN: 67960

Other (OTH) AF: 0.632 AC: 1332 AN: 2108

Alfa AF: 0.556 Hom.: 3027

Bravo AF: 0.686

Asia WGS AF: 0.454 AC: 1582 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.78
PhyloP100		1.6
PromoterAI		0.0040	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3752210; hg19: chr19-49520372; COSMIC: COSV55485532;