X-106901521-C-T

Position:

• chrX-106901521-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_138382.3(RIPPLY1):​c.249G>A​(p.Thr83=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,209,682 control chromosomes in the GnomAD database, including 6 homozygotes. There are 249 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., 109 hem., cov: 23)
  • Exomes 𝑓: 0.00042 (4 hom. 140 hem.)
• Consequence: RIPPLY1 NM_138382.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.387

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-106901521-C-T is Benign according to our data. Variant chrX-106901521-C-T is described in ClinVar as [Benign]. Clinvar id is 780717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.387 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPPLY1	NM_138382.3	c.249G>A	p.Thr83=	synonymous_variant	3/4	ENST00000276173.5
CLDN2	NM_001171092.1	c.-179+1017C>T		intron_variant
RIPPLY1	NM_001171706.2	c.156-613G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPPLY1	ENST00000276173.5	c.249G>A	p.Thr83=	synonymous_variant	3/4	1	NM_138382.3	P1
RIPPLY1	ENST00000411805.1	c.156-613G>A		intron_variant		1
CLDN2	ENST00000541806.6	c.-179+1017C>T		intron_variant		1		P1
MORC4	ENST00000604604.1	c.112-85735G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 346 AN: 111827 Hom.: 2 Cov.: 23 AF XY: 0.00321 AC XY: 109 AN XY: 34003

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00401

GnomAD3 exomes AF: 0.000790 AC: 143 AN: 180932 Hom.: 1 AF XY: 0.000596 AC XY: 40 AN XY: 67078

Gnomad AFR exome AF: 0.00896

Gnomad AMR exome AF: 0.000585

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.000148

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000866

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000424 AC: 465 AN: 1097801 Hom.: 4 Cov.: 30 AF XY: 0.000385 AC XY: 140 AN XY: 363249

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000413

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000677

Gnomad4 OTH exome AF: 0.000934

GnomAD4 genome AF: 0.00308 AC: 345 AN: 111881 Hom.: 2 Cov.: 23 AF XY: 0.00320 AC XY: 109 AN XY: 34067

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.00142

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.00396

Alfa AF: 0.00217 Hom.: 12

Bravo AF: 0.00376

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

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	Dec 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.0
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs190216177; hg19: chrX-106144751;