chr17-801020-TCTC-T

Variant names:

• chr17-801020-TCTC-T
• rs1555607285
• NM_022463.5:c.1234_1236delGAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_022463.5(NXN):​c.1234_1236delGAG​(p.Glu412del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NXN NM_022463.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99
• Publications: 0 publications found

Genes affected

NXN (HGNC:18008): (nucleoredoxin) This gene encodes a member of the thioredoxin superfamily, a group of small, multifunctional redox-active proteins. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. The encoded protein acts a redox-dependent regulator of the Wnt signaling pathway and is involved in cell growth and differentiation. [provided by RefSeq, Sep 2015]

NXN Gene-Disease associations (from GenCC):

• robinow syndrome, autosomal recessive 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive Robinow syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_022463.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-801020-TCTC-T is Pathogenic according to our data. Variant chr17-801020-TCTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 488062.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022463.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NXN	NM_022463.5	MANE Select	c.1234_1236delGAG	p.Glu412del	conservative_inframe_deletion	Exon 8 of 8	NP_071908.2
	NXN	NM_001205319.1		c.910_912delGAG	p.Glu304del	conservative_inframe_deletion	Exon 8 of 8	NP_001192248.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NXN	ENST00000336868.8	TSL:1 MANE Select	c.1234_1236delGAG	p.Glu412del	conservative_inframe_deletion	Exon 8 of 8	ENSP00000337443.3
	NXN	ENST00000575801.5	TSL:1	c.910_912delGAG	p.Glu304del	conservative_inframe_deletion	Exon 8 of 8	ENSP00000461038.1
	NXN	ENST00000571281.1	TSL:1	n.412_414delGAG		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Robinow syndrome, autosomal recessive 2 Pathogenic:1

Aug 08, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=42/58	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555607285; hg19: chr17-704260;