rs1060505054

Variant names:

• chr1-61404120-AC-A
• rs1060505054
• NM_001134673.4:c.1094delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001145512.2(NFIA):​c.1229delC​(p.Pro410HisfsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P410P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NFIA NM_001145512.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.75
• Publications: 5 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 11 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 1-61404120-AC-A is Pathogenic according to our data. Variant chr1-61404120-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 417968.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145512.2. 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
	NFIA	NM_001134673.4	MANE Select	c.1094delC	p.Pro365HisfsTer32	frameshift	Exon 8 of 11	NP_001128145.1
	NFIA	NM_001145512.2		c.1229delC	p.Pro410HisfsTer32	frameshift	Exon 9 of 12	NP_001138984.1
	NFIA	NM_001145511.2		c.1070delC	p.Pro357HisfsTer32	frameshift	Exon 8 of 11	NP_001138983.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIA	ENST00000403491.8	TSL:1 MANE Select	c.1094delC	p.Pro365HisfsTer32	frameshift	Exon 8 of 11	ENSP00000384523.3
	NFIA	ENST00000371187.7	TSL:1	c.1094delC	p.Pro365HisfsTer32	frameshift	Exon 8 of 10	ENSP00000360229.3
	NFIA	ENST00000371189.8	TSL:2	c.1229delC	p.Pro410HisfsTer32	frameshift	Exon 9 of 12	ENSP00000360231.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Brain malformations with or without urinary tract defects (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060505054; hg19: chr1-61869792;