NM_006666.3:c.1367-16T>C

Variant names:

• chr19-49015801-T-C
• rs749776
• NM_006666.3:c.1367-16T>C

Variant summary

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

The NM_006666.3(RUVBL2):​c.1367-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,613,232 control chromosomes in the GnomAD database, including 280,359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30424 hom., cov: 32)
  • Exomes 𝑓: 0.58 (249935 hom.)
• Consequence: RUVBL2 NM_006666.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0660
• Publications: 13 publications found

Genes affected

RUVBL2 (HGNC:10475): (RuvB like AAA ATPase 2) This gene encodes the second human homologue of the bacterial RuvB gene. Bacterial RuvB protein is a DNA helicase essential for homologous recombination and DNA double-strand break repair. Functional analysis showed that this gene product has both ATPase and DNA helicase activities. This gene is physically linked to the CGB/LHB gene cluster on chromosome 19q13.3, and is very close (55 nt) to the LHB gene, in the opposite orientation. [provided by RefSeq, Jul 2008]

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=-0.79).
• BP6: Variant 19-49015801-T-C is Benign according to our data. Variant chr19-49015801-T-C is described in ClinVar as Benign. ClinVar VariationId is 1277510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUVBL2	NM_006666.3	c.1367-16T>C		intron_variant	Intron 14 of 14	ENST00000595090.6	NP_006657.1
LHB	NM_000894.3	c.*267A>G		downstream_gene_variant		ENST00000649238.3	NP_000885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUVBL2	ENST00000595090.6	c.1367-16T>C		intron_variant	Intron 14 of 14	1	NM_006666.3	ENSP00000473172.1
LHB	ENST00000649238.3	c.*267A>G		downstream_gene_variant			NM_000894.3	ENSP00000497294.2

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95252 AN: 151970 Hom.: 30392 Cov.: 32

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.597

GnomAD2 exomes AF: 0.592 AC: 147970 AN: 249866 AF XY: 0.585

Gnomad AFR exome AF: 0.727

Gnomad AMR exome AF: 0.706

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: 0.586

GnomAD4 exome AF: 0.582 AC: 849875 AN: 1461144 Hom.: 249935 Cov.: 50 AF XY: 0.580 AC XY: 421754 AN XY: 726920

African (AFR) AF: 0.735 AC: 24607 AN: 33468

American (AMR) AF: 0.700 AC: 31298 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 14910 AN: 26130

East Asian (EAS) AF: 0.342 AC: 13594 AN: 39698

South Asian (SAS) AF: 0.548 AC: 47248 AN: 86230

European-Finnish (FIN) AF: 0.629 AC: 33578 AN: 53372

Middle Eastern (MID) AF: 0.643 AC: 3707 AN: 5766

European-Non Finnish (NFE) AF: 0.581 AC: 645726 AN: 1111416

Other (OTH) AF: 0.583 AC: 35207 AN: 60354

GnomAD4 genome AF: 0.627 AC: 95330 AN: 152088 Hom.: 30424 Cov.: 32 AF XY: 0.626 AC XY: 46539 AN XY: 74328

African (AFR) AF: 0.722 AC: 29944 AN: 41486

American (AMR) AF: 0.668 AC: 10214 AN: 15288

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

East Asian (EAS) AF: 0.332 AC: 1712 AN: 5162

South Asian (SAS) AF: 0.545 AC: 2623 AN: 4812

European-Finnish (FIN) AF: 0.620 AC: 6564 AN: 10584

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40284 AN: 67972

Other (OTH) AF: 0.594 AC: 1254 AN: 2110

Alfa AF: 0.621 Hom.: 3500

Bravo AF: 0.629

Asia WGS AF: 0.449 AC: 1565 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

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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
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.066
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs749776; hg19: chr19-49519058; COSMIC: COSV55484610; COSMIC: COSV55484610;