2-200893251-T-C

Variant names:

• chr2-200893251-T-C
• rs1178655685
• NM_001369441.2:c.442T>C

Variant summary

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

The NM_001369441.2(NIF3L1):​c.442T>C​(p.Cys148Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000224 in 1,340,406 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: NIF3L1 NM_001369441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

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 rank	MANE	Protein	UniProt
NIF3L1	NM_001369441.2	c.442T>C	p.Cys148Arg	missense_variant	Exon 3 of 7	ENST00000409020.6	NP_001356370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIF3L1	ENST00000409020.6	c.442T>C	p.Cys148Arg	missense_variant	Exon 3 of 7	5	NM_001369441.2	ENSP00000386394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1340406 Hom.: 0 Cov.: 30 AF XY: 0.00000303 AC XY: 2 AN XY: 659484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000854

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.442T>C (p.C148R) alteration is located in exon 3 (coding exon 2) of the NIF3L1 gene. This alteration results from a T to C substitution at nucleotide position 442, causing the cysteine (C) at amino acid position 148 to be replaced by an arginine (R). 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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;.;T;.;T;T;.;.
Eigen	Benign	-0.062
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T;T;T;.;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.074	T;T;T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T;T;T
Polyphen		0.15	.;.;B;.;B;.;.;.
Vest4		0.83, 0.81, 0.82
MutPred		0.51		.;Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);.;Gain of MoRF binding (P = 0.0052);.;Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);
MVP		0.45
MPC		0.39
ClinPred		0.75	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs1178655685; hg19: chr2-201757974;