Genetic Variant FOXD4L6:p.Arg403Lys (chr9-41127176-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_001085476.4(FOXD4L6):c.1208G>A(p.Arg403Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXD4L6
NM_001085476.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.837

Variant links:

Genes affected

FOXD4L6 (HGNC:31986): (forkhead box D4 like 6) 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]

FOXD4L6 links:

FRG1HP (HGNC:51767): (FSHD region gene 1 family member H, pseudogene)

FRG1HP 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=0.074389726).

BP6

Variant 9-41127176-C-T is Benign according to our data. Variant chr9-41127176-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2379130.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD4L6	NM_001085476.4 link	c.1208G>A	p.Arg403Lys	missense_variant	Exon 1 of 1	ENST00000622588.2	NP_001078945.1	Q3SYB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD4L6	ENST00000622588.2 link	c.1208G>A	p.Arg403Lys	missense_variant	Exon 1 of 1	6	NM_001085476.4	ENSP00000484875.1		Q3SYB3
FRG1HP	ENST00000617940.2 link	n.412-67925C>T		intron_variant	Intron 5 of 9	6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149704

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000117

AC:

AN:

59838

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

30316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000287

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000176

AC:

255

AN:

1451402

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

120

AN XY:

721790

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.000268

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000668

AC:

AN:

149704

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

72928

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000149

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 08, 2022

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

0.17

BayesDel_noAF

Benign

-0.17

CADD

Benign

7.7

DANN

Benign

0.94

DEOGEN2

Benign

0.018

LIST_S2

Benign

0.31

MetaRNN

Benign

0.074

Sift4G

Benign

0.82

Vest4

0.064

gMVP

0.0099

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