chrX-106901507-G-A

Variant names:

• chrX-106901507-G-A
• rs762242561
• NM_138382.3:c.263C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_138382.3(RIPPLY1):​c.263C>T​(p.Thr88Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,097,856 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes 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: not found (cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 7 hem.)
• Consequence: RIPPLY1 NM_138382.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1426191).
• BS2: High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY1	NM_138382.3	c.263C>T	p.Thr88Ile	missense_variant	Exon 3 of 4	ENST00000276173.5	NP_612391.1
CLDN2	NM_001171092.1	c.-179+1003G>A		intron_variant	Intron 1 of 1		NP_001164563.1
RIPPLY1	NM_001171706.2	c.156-599C>T		intron_variant	Intron 1 of 1		NP_001165177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPPLY1	ENST00000276173.5	c.263C>T	p.Thr88Ile	missense_variant	Exon 3 of 4	1	NM_138382.3	ENSP00000276173.4
CLDN2	ENST00000541806.6	c.-179+1003G>A		intron_variant	Intron 1 of 1	1		ENSP00000441283.1
RIPPLY1	ENST00000411805.1	c.156-599C>T		intron_variant	Intron 1 of 1	1		ENSP00000400539.1
MORC4	ENST00000604604.1	c.111-85721C>T		intron_variant	Intron 1 of 1	2		ENSP00000474750.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1097856 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 363300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.099
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.49	P
Vest4		0.098
MutPred		0.19		Loss of disorder (P = 0.0351);
MVP		0.17
MPC		0.066
ClinPred		0.53	D
GERP RS		2.3
Varity_R		0.057
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs762242561; hg19: chrX-106144737;