chr1-63323849-C-G

Variant names:

• chr1-63323849-C-G
• rs1647049719
• NM_012183.3:c.791C>G

Variant summary

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

The NM_012183.3(FOXD3):​c.791C>G​(p.Ala264Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXD3 NM_012183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

Genes affected

FOXD3 (HGNC:3804): (forkhead box D3) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. Mutations in this gene cause autoimmune susceptibility 1. [provided by RefSeq, Nov 2008]

FOXD3-AS1 (HGNC:40241): (FOXD3 antisense RNA 1)

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=0.39205694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD3	NM_012183.3	c.791C>G	p.Ala264Gly	missense_variant	Exon 1 of 1	ENST00000371116.4	NP_036315.1
FOXD3-AS1	NR_121637.1	n.87+506G>C		intron_variant	Intron 1 of 2
FOXD3-AS1	NR_121636.1	n.-174G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD3	ENST00000371116.4	c.791C>G	p.Ala264Gly	missense_variant	Exon 1 of 1	6	NM_012183.3	ENSP00000360157.2
FOXD3-AS1	ENST00000427268.1	n.87+506G>C		intron_variant	Intron 1 of 2	1
FOXD3-AS1	ENST00000431294.7	n.-73G>C		upstream_gene_variant		1
FOXD3-AS1	ENST00000697579.1	n.-174G>C		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.791C>G (p.A264G) alteration is located in exon 1 (coding exon 1) of the FOXD3 gene. This alteration results from a C to G substitution at nucleotide position 791, causing the alanine (A) at amino acid position 264 to be replaced by a glycine (G). 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	0.094
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Benign	0.10	T
Sift4G	Benign	0.48	T
Polyphen		0.98	D
Vest4		0.17
MutPred		0.41		Loss of helix (P = 0.0093);
MVP		0.70
ClinPred		0.40	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.45

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: rs1647049719; hg19: chr1-63789520;