1-40770737-T-C

Variant names:

• chr1-40770737-T-C
• NM_014223.5:c.917T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014223.5(NFYC):​c.917T>C​(p.Met306Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M306V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFYC NM_014223.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

NFYC (HGNC:7806): (nuclear transcription factor Y subunit gamma) This gene encodes one subunit of a trimeric complex forming a highly conserved transcription factor that binds with high specificity to CCAAT motifs in the promoters of a variety of genes. The encoded protein, subunit C, forms a tight dimer with the B subunit, a prerequisite for subunit A association. The resulting trimer binds to DNA with high specificity and affinity. Subunits B and C each contain a histone-like motif. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37307543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFYC	NM_014223.5	c.917T>C	p.Met306Thr	missense_variant	Exon 10 of 10	ENST00000447388.8	NP_055038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFYC	ENST00000447388.8	c.917T>C	p.Met306Thr	missense_variant	Exon 10 of 10	1	NM_014223.5	ENSP00000404427.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.974T>C (p.M325T) alteration is located in exon 11 (coding exon 10) of the NFYC gene. This alteration results from a T to C substitution at nucleotide position 974, causing the methionine (M) at amino acid position 325 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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;.;.;.;.;.;.;.;.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;D;D;.;D;D;.;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	.;.;.;.;.;.;.;.;.;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.69	T;T;T;T;T;T;D;T;T;D
Polyphen		0.15, 0.98, 0.98	.;B;.;.;B;.;D;B;B;D
Vest4		0.76
MutPred		0.27		.;.;.;.;.;.;.;.;.;Loss of stability (P = 0.0314);
MVP		0.35
MPC		1.0
ClinPred		0.70	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-41236409;