Genetic Variant FOXD4L5:p.Cys371Phe (chr9-65283266-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001126334.1(FOXD4L5):c.1112G>T(p.Cys371Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C371S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXD4L5
NM_001126334.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.224

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.120993346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126334.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L5	NM_001126334.1	MANE Select	c.1112G>T	p.Cys371Phe	missense	Exon 1 of 1	NP_001119806.1	Q5VV16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L5	ENST00000377420.1	TSL:6 MANE Select	c.1112G>T	p.Cys371Phe	missense	Exon 1 of 1	ENSP00000366637.1	Q5VV16

Frequencies

GnomAD3 genomes

AF:

0.0000154

AC:

AN:

129738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000569

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1455572

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723410

African (AFR)

AF:

0.00

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39264

South Asian (SAS)

AF:

0.00

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108732

Other (OTH)

AF:

0.00

AC:

AN:

60012

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000154

AC:

AN:

129738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

62102

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000569

AC:

AN:

35146

American (AMR)

AF:

0.00

AC:

AN:

12396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3250

East Asian (EAS)

AF:

0.00

AC:

AN:

3206

South Asian (SAS)

AF:

0.00

AC:

AN:

3230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62002

Other (OTH)

AF:

0.00

AC:

AN:

1608

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0011

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.015

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.38

M_CAP

Benign

0.083

MetaRNN

Benign

0.12

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.90

PhyloP100

0.22

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.21

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

0.70

Vest4

0.19

MutPred

0.32

Loss of ubiquitination at K373 (P = 0.0584)

MVP

0.44

ClinPred

0.17

GERP RS

1.1

Varity_R

0.67

gMVP

0.043

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over