Genetic Variant FOXD4L6:p.Cys384Tyr (chr9-41127233-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001085476.4(FOXD4L6):c.1151G>A(p.Cys384Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000549 in 149,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C384R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000092 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXD4L6
NM_001085476.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.396

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08828199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD4L6	NM_001085476.4 link	c.1151G>A	p.Cys384Tyr	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.1151G>A	p.Cys384Tyr	missense_variant	Exon 1 of 1	6	NM_001085476.4	ENSP00000484875.1		Q3SYB3
FRG1HP	ENST00000617940.2 link	n.412-67868C>T		intron_variant	Intron 5 of 9	6

Frequencies

GnomAD3 genomes

AF:

0.000549

AC:

AN:

149394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000335

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:

0.0000297

Gnomad OTH

AF:

0.000490

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000919

AC:

134

AN:

1458634

Hom.:

Cov.:

AF XY:

0.0000813

AC XY:

AN XY:

725676

show subpopulations

Gnomad4 AFR exome

AF:

0.00289

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000549

AC:

AN:

149496

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

AN XY:

72956

show subpopulations

Gnomad4 AFR

AF:

0.00184

Gnomad4 AMR

AF:

0.000335

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000297

Gnomad4 OTH

AF:

0.000485

Alfa

AF:

0.000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1151G>A (p.C384Y) alteration is located in exon 1 (coding exon 1) of the FOXD4L6 gene. This alteration results from a G to A substitution at nucleotide position 1151, causing the cysteine (C) at amino acid position 384 to be replaced by a tyrosine (Y). 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

0.22

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.015

LIST_S2

Benign

0.36

MetaRNN

Benign

0.088

Sift4G

Uncertain

0.043

Vest4

0.14

gMVP

0.0096

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