1-40770736-A-G

Variant names:

• chr1-40770736-A-G
• rs779245902
• NM_014223.5:c.916A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014223.5(NFYC):​c.916A>G​(p.Met306Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: NFYC NM_014223.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22010133).
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFYC	NM_014223.5	c.916A>G	p.Met306Val	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.916A>G	p.Met306Val	missense_variant	Exon 10 of 10	1	NM_014223.5	ENSP00000404427.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251000 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135712

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: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 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: 0.0000563

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.973A>G (p.M325V) alteration is located in exon 11 (coding exon 10) of the NFYC gene. This alteration results from a A to G substitution at nucleotide position 973, causing the methionine (M) at amino acid position 325 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.087	.;.;.;.;.;.;.;.;.;T
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;.;D;D;.;D;D;.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;.;.;.;.;.;.;.;.;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.70	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.85	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0060, 0.57, 0.66	.;B;.;.;B;.;P;B;B;P
Vest4		0.53
MVP		0.65
MPC		0.83
ClinPred		0.20	T
GERP RS		5.5
Varity_R		0.74
gMVP		0.17

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: rs779245902; hg19: chr1-41236408;