rs1553149206

Positions:

• chr1-61088426-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001134673.4(NFIA):​c.307dup​(p.Cys103LeufsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIA NM_001134673.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.624

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 1-61088426-G-GT is Pathogenic according to our data. Variant chr1-61088426-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 520892.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIA	NM_001134673.4	c.307dup	p.Cys103LeufsTer16	frameshift_variant	2/11	ENST00000403491.8	NP_001128145.1
NFIA	NM_001145511.2	c.283dup	p.Cys95LeufsTer16	frameshift_variant	2/11		NP_001138983.1
NFIA	NM_001145512.2	c.442dup	p.Cys148LeufsTer16	frameshift_variant	3/12		NP_001138984.1
NFIA	NM_005595.5	c.307dup	p.Cys103LeufsTer16	frameshift_variant	2/10		NP_005586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFIA	ENST00000403491.8	c.307dup	p.Cys103LeufsTer16	frameshift_variant	2/11	1	NM_001134673.4	ENSP00000384523	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2016

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Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553149206; hg19: chr1-61554098;