X-106900765-T-A

Position:

• chrX-106900765-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138382.3(RIPPLY1):​c.440A>T​(p.Asp147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,095,983 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000038 (0 hom. 10 hem.)
• Consequence: RIPPLY1 NM_138382.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06554642).
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPPLY1	NM_138382.3	c.440A>T	p.Asp147Val	missense_variant	4/4	ENST00000276173.5
RIPPLY1	NM_001171706.2	c.299A>T	p.Asp100Val	missense_variant	2/2
CLDN2	NM_001171092.1	c.-179+261T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPPLY1	ENST00000276173.5	c.440A>T	p.Asp147Val	missense_variant	4/4	1	NM_138382.3	P1
RIPPLY1	ENST00000411805.1	c.299A>T	p.Asp100Val	missense_variant	2/2	1
CLDN2	ENST00000541806.6	c.-179+261T>A		intron_variant		1		P1
MORC4	ENST00000604604.1	c.112-84979A>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000229 AC: 4 AN: 174987 Hom.: 0 AF XY: 0.0000324 AC XY: 2 AN XY: 61723

Gnomad AFR exome AF: 0.00

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: 0.0000513

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 42 AN: 1095983 Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 10 AN XY: 361685

Gnomad4 AFR exome AF: 0.0000379

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: 0.0000476

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.440A>T (p.D147V) alteration is located in exon 4 (coding exon 4) of the RIPPLY1 gene. This alteration results from a A to T substitution at nucleotide position 440, causing the aspartic acid (D) at amino acid position 147 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.5
DANN	Benign	0.84
DEOGEN2	Uncertain	0.45	T;.
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.38	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.063
Sift	Benign	0.039	D;D
Sift4G	Benign	0.082	T;D
Polyphen		0.0020	B;B
Vest4		0.091
MutPred		0.12		Gain of ubiquitination at K151 (P = 0.0568);.;
MVP		0.088
MPC		0.035
ClinPred		0.076	T
GERP RS		3.7
Varity_R		0.30
gMVP		0.14

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: rs759317535; hg19: chrX-106143995;