2-200897146-T-C

Position:

• chr2-200897146-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001369441.2(NIF3L1):​c.797T>C​(p.Ile266Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NIF3L1 NM_001369441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61

Genes affected

NIF3L1 (HGNC:13390): (NGG1 interacting factor 3 like 1) Enables identical protein binding activity. Involved in positive regulation of transcription, DNA-templated. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIF3L1	NM_001369441.2	c.797T>C	p.Ile266Thr	missense_variant	5/7	ENST00000409020.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIF3L1	ENST00000409020.6	c.797T>C	p.Ile266Thr	missense_variant	5/7	5	NM_001369441.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249484 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.797T>C (p.I266T) alteration is located in exon 5 (coding exon 4) of the NIF3L1 gene. This alteration results from a T to C substitution at nucleotide position 797, causing the isoleucine (I) at amino acid position 266 to be replaced by a threonine (T). 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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;T
Eigen	Benign	-0.034
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.69	T;T;.
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.026	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.23	B;.;B
Vest4		0.39
MutPred		0.83		Loss of stability (P = 0.0044);.;Loss of stability (P = 0.0044);
MVP		0.38
MPC		0.058
ClinPred		0.86	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28

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: rs946545663; hg19: chr2-201761869;