16-28963727-T-G

Variant names:

• chr16-28963727-T-G
• NM_032815.4:c.1124T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032815.4(NFATC2IP):​c.1124T>G​(p.Met375Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NFATC2IP NM_032815.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82

Genes affected

NFATC2IP (HGNC:25906): (nuclear factor of activated T cells 2 interacting protein) Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NFATC2IP-AS1 (HGNC:56085): (NFATC2IP antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFATC2IP	NM_032815.4	c.1124T>G	p.Met375Arg	missense_variant	Exon 8 of 8	ENST00000320805.9	NP_116204.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFATC2IP	ENST00000320805.9	c.1124T>G	p.Met375Arg	missense_variant	Exon 8 of 8	1	NM_032815.4	ENSP00000324792.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461762 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1124T>G (p.M375R) alteration is located in exon 8 (coding exon 8) of the NFATC2IP gene. This alteration results from a T to G substitution at nucleotide position 1124, causing the methionine (M) at amino acid position 375 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.80
MutPred		0.60		.;Loss of glycosylation at T373 (P = 0.0746);.;
MVP		0.60
MPC		1.2
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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: chr16-28975048;