NM_138382.3:c.362A>C

Variant names:

• chrX-106900843-T-G
• rs41306259
• NM_138382.3:c.362A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138382.3(RIPPLY1):​c.362A>C​(p.Asn121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,053 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N121S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RIPPLY1 NM_138382.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37892026).

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.362A>C	p.Asn121Thr	missense	Exon 4 of 4	NP_612391.1	Q0D2K3-1
	RIPPLY1	NM_001171706.2		c.221A>C	p.Asn74Thr	missense	Exon 2 of 2	NP_001165177.1	Q0D2K3-2
	CLDN2	NM_001171092.1		c.-179+339T>G		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.362A>C	p.Asn121Thr	missense	Exon 4 of 4	ENSP00000276173.4	Q0D2K3-1
	RIPPLY1	ENST00000411805.1	TSL:1	c.221A>C	p.Asn74Thr	missense	Exon 2 of 2	ENSP00000400539.1	Q0D2K3-2
	CLDN2	ENST00000541806.6	TSL:1	c.-179+339T>G		intron	N/A	ENSP00000441283.1	P57739

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098053 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363483

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841986

Other (OTH) AF: 0.00 AC: 0 AN: 46081

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.89	P
Vest4		0.40
MutPred		0.36		Gain of glycosylation at N121 (P = 0.0474)
MVP		0.69
MPC		0.21
ClinPred		0.97	D
GERP RS		2.5
Varity_R		0.42
gMVP		0.32
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41306259; hg19: chrX-106144073;