chr9-41127218-C-T

Variant names:

• chr9-41127218-C-T
• rs1173913070
• NM_001085476.4:c.1166G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001085476.4(FOXD4L6):​c.1166G>A​(p.Ser389Asn) 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. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L6 NM_001085476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11149904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD4L6	NM_001085476.4	c.1166G>A	p.Ser389Asn	missense_variant	Exon 1 of 1	ENST00000622588.2	NP_001078945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD4L6	ENST00000622588.2	c.1166G>A	p.Ser389Asn	missense_variant	Exon 1 of 1	6	NM_001085476.4	ENSP00000484875.1
FRG1HP	ENST00000617940.2	n.412-67883C>T		intron_variant	Intron 5 of 9	6

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459262 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1166G>A (p.S389N) 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 1166, causing the serine (S) at amino acid position 389 to be replaced by an asparagine (N). 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	0.19
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.11	T
Sift4G	Uncertain	0.038	D
Vest4		0.18
gMVP		0.0093

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

Other links and lift over

dbSNP: rs1173913070; hg19: chr9-70919033;