rs1553149202

Variant names:

• chr1-61088412-G-GA
• rs1553149202
• NM_001134673.4:c.297dupA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001134673.4(NFIA):​c.297dupA​(p.Pro100ThrfsTer19) variant causes a frameshift 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIA NM_001134673.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

NFIA (HGNC:7784): (nuclear factor I A) This gene encodes a member of the NF1 (nuclear factor 1) family of transcription factors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

NFIA Gene-Disease associations (from GenCC):

• brain malformations with or without urinary tract defects

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• chromosome 1p32-p31 deletion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-61088412-G-GA is Pathogenic according to our data. Variant chr1-61088412-G-GA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 435980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIA	NM_001134673.4	c.297dupA	p.Pro100ThrfsTer19	frameshift_variant	Exon 2 of 11	ENST00000403491.8	NP_001128145.1
NFIA	NM_001145512.2	c.432dupA	p.Pro145ThrfsTer19	frameshift_variant	Exon 3 of 12		NP_001138984.1
NFIA	NM_001145511.2	c.273dupA	p.Pro92ThrfsTer19	frameshift_variant	Exon 2 of 11		NP_001138983.1
NFIA	NM_005595.5	c.297dupA	p.Pro100ThrfsTer19	frameshift_variant	Exon 2 of 10		NP_005586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFIA	ENST00000403491.8	c.297dupA	p.Pro100ThrfsTer19	frameshift_variant	Exon 2 of 11	1	NM_001134673.4	ENSP00000384523.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chromosome 1p32-p31 deletion syndrome Pathogenic:2

Jan 20, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	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: rs1553149202; hg19: chr1-61554084;