NM_001085476.4:c.1151G>A

Variant names:

• chr9-41127233-C-T
• rs1361474113
• NM_001085476.4:c.1151G>A

Variant summary

Our verdict is Likely benign. The variant received -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. 7/10 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.396
• Publications: 0 publications found

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]

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

ENSG00000308937 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.08828199).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085476.4. 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
	FOXD4L6	NM_001085476.4	MANE Select	c.1151G>A	p.Cys384Tyr	missense	Exon 1 of 1	NP_001078945.1	Q3SYB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L6	ENST00000622588.2	TSL:6 MANE Select	c.1151G>A	p.Cys384Tyr	missense	Exon 1 of 1	ENSP00000484875.1	Q3SYB3
	FRG1HP	ENST00000617940.2	TSL:6	n.412-67868C>T		intron	N/A
	ENSG00000308937	ENST00000837379.1		n.683+1595C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000549 AC: 82 AN: 149394 Hom.: 0 Cov.: 26

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.: 0 Cov.: 35 AF XY: 0.0000813 AC XY: 59 AN XY: 725676

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

African (AFR) AF: 0.00289 AC: 95 AN: 32838

American (AMR) AF: 0.000403 AC: 18 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111516

Other (OTH) AF: 0.000133 AC: 8 AN: 60138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000549 AC: 82 AN: 149496 Hom.: 0 Cov.: 26 AF XY: 0.000589 AC XY: 43 AN XY: 72956

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

African (AFR) AF: 0.00184 AC: 74 AN: 40302

American (AMR) AF: 0.000335 AC: 5 AN: 14946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.00 AC: 0 AN: 4696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67358

Other (OTH) AF: 0.000485 AC: 1 AN: 2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.015	T
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.088	T
PhyloP100		-0.40
Sift4G	Uncertain	0.043	D
Vest4		0.14
gMVP		0.0096
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1361474113; hg19: chr9-70919018;