1-61081990-C-T

Position:

• chr1-61081990-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001145512.2(NFIA):​c.47C>T​(p.Thr16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFIA NM_001145512.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.832

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFIA. . Gene score misZ 3.231 (greater than the threshold 3.09). Trascript score misZ 3.286 (greater than threshold 3.09). GenCC has associacion of gene with chromosome 1p32-p31 deletion syndrome, brain malformations with or without urinary tract defects.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1190297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIA	NM_001145512.2	c.47C>T	p.Thr16Met	missense_variant	1/12		NP_001138984.1
NFIA	NM_001145511.2	c.3+4362C>T		intron_variant			NP_001138983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFIA	ENST00000371189.8	c.47C>T	p.Thr16Met	missense_variant	1/12	2		ENSP00000360231
NFIA	ENST00000371191.5	c.97-6159C>T		intron_variant		5		ENSP00000360233
NFIA	ENST00000407417.7	c.3+4362C>T		intron_variant		2		ENSP00000384680

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported using an alternate transcript of the gene -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.95
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.081
Sift	Benign	0.042	D
Sift4G	Uncertain	0.023	D
Vest4		0.30
MutPred		0.18		Loss of glycosylation at T16 (P = 0.0029);
MVP		0.18
MPC		0.86
ClinPred		0.27	T
GERP RS		2.7
gMVP		0.49

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-61547662;