NM_138382.3:c.393C>T

Variant names:

• chrX-106900812-G-A
• rs187005190
• NM_138382.3:c.393C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138382.3(RIPPLY1):​c.393C>T​(p.Tyr131Tyr) 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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 130 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138382.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY1	NM_138382.3	MANE Select	c.393C>T	p.Tyr131Tyr	synonymous	Exon 4 of 4	NP_612391.1	Q0D2K3-1
	RIPPLY1	NM_001171706.2		c.252C>T	p.Tyr84Tyr	synonymous	Exon 2 of 2	NP_001165177.1	Q0D2K3-2
	CLDN2	NM_001171092.1		c.-179+308G>A		intron	N/A	NP_001164563.1	P57739

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY1	ENST00000276173.5	TSL:1 MANE Select	c.393C>T	p.Tyr131Tyr	synonymous	Exon 4 of 4	ENSP00000276173.4	Q0D2K3-1
	RIPPLY1	ENST00000411805.1	TSL:1	c.252C>T	p.Tyr84Tyr	synonymous	Exon 2 of 2	ENSP00000400539.1	Q0D2K3-2
	CLDN2	ENST00000541806.6	TSL:1	c.-179+308G>A		intron	N/A	ENSP00000441283.1	P57739

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 485 AN: 111609 Hom.: 2 Cov.: 23

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

GnomAD2 exomes AF: 0.00114 AC: 207 AN: 181027 AF XY: 0.000864

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 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

African (AFR) AF: 0.0173 AC: 456 AN: 26401

American (AMR) AF: 0.000369 AC: 13 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54123

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4135

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 841844

Other (OTH) AF: 0.000673 AC: 31 AN: 46075

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

African (AFR) AF: 0.0155 AC: 476 AN: 30664

American (AMR) AF: 0.000379 AC: 4 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6059

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53161

Other (OTH) AF: 0.00330 AC: 5 AN: 1517

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.00494

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.3
DANN	Benign	0.76
PhyloP100		0.99
Mutation Taster		=98/2	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: rs187005190; hg19: chrX-106144042; COSMIC: COSV105004977;