9-41127612-G-T

Variant names:

• chr9-41127612-G-T
• rs1406180277
• NM_001085476.4:c.772C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001085476.4(FOXD4L6):​c.772C>A​(p.Arg258Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/10 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. R258G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L6 NM_001085476.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09431535).

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.772C>A	p.Arg258Ser	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.772C>A	p.Arg258Ser	missense	Exon 1 of 1	ENSP00000484875.1	Q3SYB3
	FRG1HP	ENST00000617940.2	TSL:6	n.412-67489G>T		intron	N/A
	ENSG00000308937	ENST00000837379.1		n.683+1974G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1175586 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 590606

African (AFR) AF: 0.00 AC: 0 AN: 26928

American (AMR) AF: 0.00 AC: 0 AN: 35234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22568

East Asian (EAS) AF: 0.00 AC: 0 AN: 35852

South Asian (SAS) AF: 0.00 AC: 0 AN: 73944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3562

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 891922

Other (OTH) AF: 0.00 AC: 0 AN: 50836

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.026	T
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.094	T
PhyloP100		-0.10
Sift4G	Benign	0.94	T
Vest4		0.13
gMVP		0.11

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: rs1406180277; hg19: chr9-70918639;