X-106900812-G-A

Position:

• chrX-106900812-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138382.3(RIPPLY1):​c.393C>T​(p.Tyr131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000829 in 1,209,537 control chromosomes in the GnomAD database, including 5 homozygotes. There are 258 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., 128 hem., cov: 23)
  • Exomes 𝑓: 0.00047 (3 hom. 130 hem.)
• Consequence: RIPPLY1 NM_138382.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.993

Genes affected

RIPPLY1 (HGNC:25117): (ripply transcriptional repressor 1) This gene encodes a protein similar to a zebrafish protein which acts as a transcriptional repressor in and is required for somite segmentation in zebrafish embryos (PMID: 16326386). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

CLDN2 (HGNC:2041): (claudin 2) This gene product belongs to the claudin protein family whose members have been identified as major integral membrane proteins localized exclusively at tight junctions. Claudins are expressed in an organ-specific manner and regulate tissue-specific physiologic properties of tight junctions. This protein is expressed in the intestine. Alternatively spliced transcript variants with different 5' untranslated region have been found for this gene.[provided by RefSeq, Jan 2010]

MORC4 (HGNC:23485): (MORC family CW-type zinc finger 4) In human, the four current members of the microrchidia (morc) gene family share an N-terminal ATPase-like ATP-binding region and a CW four-cysteine zinc-finger motif. The protein encoded by this gene also has a nuclear matrix binding domain and a two-stranded coiled-coil motif near its C-terminus. This gene is widely expressed at low levels in normal tissues and has elevated expression in placenta and testis. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant X-106900812-G-A is Benign according to our data. Variant chrX-106900812-G-A is described in ClinVar as [Benign]. Clinvar id is 786709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.993 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000472 (518/1097875) while in subpopulation AFR AF= 0.0173 (456/26401). AF 95% confidence interval is 0.016. There are 3 homozygotes in gnomad4_exome. There are 130 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPPLY1	NM_138382.3	c.393C>T	p.Tyr131=	synonymous_variant	4/4	ENST00000276173.5
RIPPLY1	NM_001171706.2	c.252C>T	p.Tyr84=	synonymous_variant	2/2
CLDN2	NM_001171092.1	c.-179+308G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPPLY1	ENST00000276173.5	c.393C>T	p.Tyr131=	synonymous_variant	4/4	1	NM_138382.3	P1
RIPPLY1	ENST00000411805.1	c.252C>T	p.Tyr84=	synonymous_variant	2/2	1
CLDN2	ENST00000541806.6	c.-179+308G>A		intron_variant		1		P1
MORC4	ENST00000604604.1	c.112-85026C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 485 AN: 111609 Hom.: 2 Cov.: 23 AF XY: 0.00378 AC XY: 128 AN XY: 33833

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00114 AC: 207 AN: 181027 Hom.: 1 AF XY: 0.000864 AC XY: 58 AN XY: 67143

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.000402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000472 AC: 518 AN: 1097875 Hom.: 3 Cov.: 30 AF XY: 0.000358 AC XY: 130 AN XY: 363307

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.000369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.00434 AC: 485 AN: 111662 Hom.: 2 Cov.: 23 AF XY: 0.00378 AC XY: 128 AN XY: 33896

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.000379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00330

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.00494

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.3
DANN	Benign	0.76

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: rs187005190; hg19: chrX-106144042; COSMIC: COSV105004977;