Genetic Variant FOXD4L5:p.Arg414Pro (chr9-65283137-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001126334.1(FOXD4L5):c.1241G>C(p.Arg414Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 9)

Exomes 𝑓: 0.00031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXD4L5
NM_001126334.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.86

Variant links:

Genes affected

FOXD4L5 (HGNC:18522): (forkhead box D4 like 5) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anatomical structure morphogenesis; cell differentiation; and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

FOXD4L5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013286352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD4L5	NM_001126334.1 link	c.1241G>C	p.Arg414Pro	missense_variant	Exon 1 of 1	ENST00000377420.1	NP_001119806.1	Q5VV16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD4L5	ENST00000377420.1 link	c.1241G>C	p.Arg414Pro	missense_variant	Exon 1 of 1	6	NM_001126334.1	ENSP00000366637.1		Q5VV16

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

51274

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000420

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0149

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000847

Gnomad OTH

AF:

0.00156

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000307

AC:

276

AN:

899946

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

136

AN XY:

453056

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00765

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000335

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000546

AC:

AN:

51320

Hom.:

Cov.:

AF XY:

0.000560

AC XY:

AN XY:

23202

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000419

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0150

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000848

Gnomad4 OTH

AF:

0.00153

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1241G>C (p.R414P) alteration is located in exon 1 (coding exon 1) of the FOXD4L5 gene. This alteration results from a G to C substitution at nucleotide position 1241, causing the arginine (R) at amino acid position 414 to be replaced by a proline (P). 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

-0.0038

BayesDel_noAF

Benign

-0.24

CADD

Benign

9.7

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.011

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.010

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.84

Vest4

0.16

MutPred

0.17

Gain of glycosylation at R414 (P = 0.0029);

MVP

0.16

ClinPred

0.40

Varity_R

0.13

gMVP

0.028

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

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