Genetic Variant FOXD4L5:p.Thr396Met (chr9-65283191-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001126334.1(FOXD4L5):c.1187C>T(p.Thr396Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 11)

Exomes 𝑓: 0.00017 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

FOXD4L5
NM_001126334.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.75

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044835806).

BP6

Variant 9-65283191-G-A is Benign according to our data. Variant chr9-65283191-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2361597.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD4L5	NM_001126334.1 link	c.1187C>T	p.Thr396Met	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.1187C>T	p.Thr396Met	missense_variant	Exon 1 of 1	6	NM_001126334.1	ENSP00000366637.1		Q5VV16

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

211

AN:

88478

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00857

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000636

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

GnomAD3 exomes

AF:

0.0300

AC:

AN:

2070

Hom.:

AF XY:

0.0353

AC XY:

AN XY:

850

show subpopulations

Gnomad AFR exome

AF:

0.0323

Gnomad AMR exome

AF:

0.0216

Gnomad SAS exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000171

AC:

211

AN:

1233504

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

614878

show subpopulations

Gnomad4 AFR exome

AF:

0.00590

Gnomad4 AMR exome

AF:

0.000250

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000132

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000744

Gnomad4 OTH exome

AF:

0.000501

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00238

AC:

211

AN:

88572

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

AN XY:

40882

show subpopulations

Gnomad4 AFR

AF:

0.00854

Gnomad4 AMR

AF:

0.000635

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 01, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

2.9

DANN

Benign

0.93

DEOGEN2

Benign

0.025

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.69

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

REVEL

Benign

0.28

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.033

Polyphen

0.064

Vest4

0.066

MutPred

0.19

Loss of relative solvent accessibility (P = 0.0071);

ClinPred

0.077

GERP RS

-0.34

Varity_R

0.031

gMVP

0.023

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