chr1-61082038-C-T

Position:

• chr1-61082038-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001145512.2(NFIA):​c.95C>T​(p.Pro32Leu) 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: 0.347

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 3 ACMG points.

• PM1: In a DNA_binding_region CTF/NF-I (size 193) in uniprot entity NFIA_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_001145512.2
• 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=0.115192324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIA	NM_001145512.2	c.95C>T	p.Pro32Leu	missense_variant	1/12
NFIA	NM_001145511.2	c.3+4410C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIA	ENST00000371189.8	c.95C>T	p.Pro32Leu	missense_variant	1/12	2
NFIA	ENST00000371191.5	c.97-6111C>T		intron_variant		5
NFIA	ENST00000407417.7	c.3+4410C>T		intron_variant		2

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2021

The c.95C>T (p.P32L) alteration is located in exon 1 (coding exon 1) of the NFIA gene. This alteration results from a C to T substitution at nucleotide position 95, causing the proline (P) at amino acid position 32 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.76	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.015
Sift	Benign	0.12	T
Sift4G	Uncertain	0.059	T
Vest4		0.22
MutPred		0.25		Loss of glycosylation at P32 (P = 0.0018);
MVP		0.22
MPC		0.85
ClinPred		0.55	D
GERP RS		2.7
gMVP		0.21

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1570105997; hg19: chr1-61547710;