chr19-13081679-GGGAGCCCCCGGGCCACA-G

Variant names:

• chr19-13081679-GGGAGCCCCCGGGCCACA-G
• rs797045737
• NM_001365902.3:c.1080_1096delGAGCCCCCGGGCCACAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001365902.3(NFIX):​c.1080_1096delGAGCCCCCGGGCCACAG​(p.Ser361fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIX NM_001365902.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.37
• Publications: 0 publications found

Genes affected

NFIX (HGNC:7788): (nuclear factor I X) The protein encoded by this gene is a transcription factor that binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3 in viral and cellular promoters. The encoded protein can also stimulate adenovirus replication in vitro. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

NFIX Gene-Disease associations (from GenCC):

• Malan overgrowth syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Illumina
• Marshall-Smith syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, G2P, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-13081679-GGGAGCCCCCGGGCCACA-G is Pathogenic according to our data. Variant chr19-13081679-GGGAGCCCCCGGGCCACA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 211591.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365902.3. 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
	NFIX	NM_001365902.3	MANE Select	c.1080_1096delGAGCCCCCGGGCCACAG	p.Ser361fs	frameshift splice_region	Exon 8 of 11	NP_001352831.1
	NFIX	NM_001378405.1		c.1128_1144delGAGCCCCCGGGCCACAG	p.Ser377fs	frameshift splice_region	Exon 8 of 11	NP_001365334.1
	NFIX	NM_001271043.2		c.1104_1120delGAGCCCCCGGGCCACAG	p.Ser369fs	frameshift splice_region	Exon 8 of 11	NP_001257972.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	ENST00000592199.6	TSL:5 MANE Select	c.1080_1096delGAGCCCCCGGGCCACAG	p.Ser361fs	frameshift splice_region	Exon 8 of 11	ENSP00000467512.1
	NFIX	ENST00000587260.1	TSL:1	c.1077_1093delGAGCCCCCGGGCCACAG	p.Ser360fs	frameshift splice_region	Exon 7 of 9	ENSP00000467785.1
	NFIX	ENST00000587760.5	TSL:1	c.1056_1072delGAGCCCCCGGGCCACAG	p.Ser353fs	frameshift splice_region	Exon 8 of 10	ENSP00000466389.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Marshall-Smith syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045737; hg19: chr19-13192493;