1-63323462-C-G

Position:

• chr1-63323462-C-G

Variant summary

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

The NM_012183.3(FOXD3):​c.404C>G​(p.Pro135Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXD3 NM_012183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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=0.2788862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXD3	NM_012183.3	c.404C>G	p.Pro135Arg	missense_variant	1/1	ENST00000371116.4
FOXD3-AS1	NR_121637.1	n.87+893G>C		intron_variant, non_coding_transcript_variant
FOXD3-AS1	NR_121636.1	n.185+29G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXD3	ENST00000371116.4	c.404C>G	p.Pro135Arg	missense_variant	1/1		NM_012183.3	P1
FOXD3-AS1	ENST00000427268.1	n.87+893G>C		intron_variant, non_coding_transcript_variant		1
FOXD3-AS1	ENST00000431294.7	n.286+29G>C		intron_variant, non_coding_transcript_variant		1
FOXD3-AS1	ENST00000697579.1	n.203+11G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.404C>G (p.P135R) 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 404, causing the proline (P) at amino acid position 135 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	0.65
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Benign	0.042	D
Sift4G	Uncertain	0.056	T
Polyphen		0.85	P
Vest4		0.067
MutPred		0.26		Loss of glycosylation at P135 (P = 0.0058);
MVP		0.49
ClinPred		0.59	D
GERP RS		2.6
Varity_R		0.18
gMVP		0.83

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: rs1175624844; hg19: chr1-63789133;