Genetic Variant FOXD1:p.Pro396_Val397insSerPro (chr5-73447175-C-CGGCGAG) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BP6BS2

The NM_004472.3(FOXD1):c.1182_1187dupCTCGCC(p.Pro396_Val397insSerPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,063,614 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 12 hom. )

Consequence

FOXD1
NM_004472.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.573

Variant links:

Genes affected

FOXD1 (HGNC:3802): (forkhead box D1) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. Studies of the orthologous mouse protein indicate that it functions in kidney development by promoting nephron progenitor differentiation, and it also functions in the development of the retina and optic chiasm. It may also regulate inflammatory reactions and prevent autoimmunity. [provided by RefSeq, Apr 2014]

FOXD1 links:

FOXD1-AS1 (HGNC:50658): (FOXD1 antisense RNA 1)

FOXD1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004472.3.

BP6

Variant 5-73447175-C-CGGCGAG is Benign according to our data. Variant chr5-73447175-C-CGGCGAG is described in ClinVar as [Likely_benign]. Clinvar id is 3029712.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD1	NM_004472.3 link	c.1182_1187dupCTCGCC	p.Pro396_Val397insSerPro	disruptive_inframe_insertion	Exon 1 of 1	ENST00000615637.3	NP_004463.1	Q16676

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXD1	ENST00000615637.3 link	c.1182_1187dupCTCGCC	p.Pro396_Val397insSerPro	disruptive_inframe_insertion	Exon 1 of 1	6	NM_004472.3	ENSP00000481581.1	Q16676
FOXD1	ENST00000513595.1 link	n.-193_-188dupCTCGCC		upstream_gene_variant		3
FOXD1-AS1	ENST00000514661.1 link	n.191_192insGGCGAG		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00355

AC:

521

AN:

146576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.0155

Gnomad AMR

AF:

0.00758

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.00456

Gnomad OTH

AF:

0.00742

GnomAD4 exome

AF:

0.00499

AC:

4576

AN:

916932

Hom.:

Cov.:

AF XY:

0.00493

AC XY:

2127

AN XY:

431388

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.00573

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00534

Gnomad4 OTH exome

AF:

0.00460

GnomAD4 genome

AF:

0.00356

AC:

522

AN:

146682

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

227

AN XY:

71410

show subpopulations

Gnomad4 AFR

AF:

0.00193

Gnomad4 AMR

AF:

0.00757

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00456

Gnomad4 OTH

AF:

0.00734

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

FOXD1-related disorder

Benign:1

May 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over