X-106903194-G-C

Variant names:

• chrX-106903194-G-C
• rs375592382
• NM_138382.3:c.94C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138382.3(RIPPLY1):​c.94C>G​(p.Pro32Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000355 in 112,644 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 23)
• Consequence: RIPPLY1 NM_138382.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22650194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY1	NM_138382.3	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 4	ENST00000276173.5	NP_612391.1
RIPPLY1	NM_001171706.2	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 2		NP_001165177.1
CLDN2	NM_001171092.1	c.-179+2690G>C		intron_variant	Intron 1 of 1		NP_001164563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPPLY1	ENST00000276173.5	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 4	1	NM_138382.3	ENSP00000276173.4
RIPPLY1	ENST00000411805.1	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 2	1		ENSP00000400539.1
CLDN2	ENST00000541806.6	c.-179+2690G>C		intron_variant	Intron 1 of 1	1		ENSP00000441283.1
MORC4	ENST00000604604.1	c.111-87408C>G		intron_variant	Intron 1 of 1	2		ENSP00000474750.1

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112644 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34800

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.00000564 AC: 1 AN: 177334 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64852

Gnomad AFR exome AF: 0.0000816

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112644 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34800

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.00

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: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;.
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;D
REVEL	Benign	0.070
Sift	Benign	0.11	T;D
Sift4G	Benign	0.098	T;T
Polyphen		0.93	P;P
Vest4		0.22
MVP		0.52
MPC		0.028
ClinPred		0.19	T
GERP RS		4.3
Varity_R		0.089
gMVP		0.15

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: rs375592382; hg19: chrX-106146424;