chr9-65283208-G-C

Variant names:

• chr9-65283208-G-C
• NM_001126334.1:c.1170C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001126334.1(FOXD4L5):​c.1170C>G​(p.Ile390Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 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. I390S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., cov: 11)
  • Exomes 𝑓: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L5 NM_001126334.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0810
• Publications: 0 publications found

Genes affected

FOXD4L5 (HGNC:18522): (forkhead box D4 like 5) 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.07990873).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126334.1. 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
	FOXD4L5	NM_001126334.1	MANE Select	c.1170C>G	p.Ile390Met	missense	Exon 1 of 1	NP_001119806.1	Q5VV16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L5	ENST00000377420.1	TSL:6 MANE Select	c.1170C>G	p.Ile390Met	missense	Exon 1 of 1	ENSP00000366637.1	Q5VV16

Frequencies

GnomAD3 genomes AF: 0.0000109 AC: 1 AN: 91834 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.0000409

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000230 AC: 3 AN: 1303442 Hom.: 0 Cov.: 22 AF XY: 0.00000307 AC XY: 2 AN XY: 650698

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

African (AFR) AF: 0.0000339 AC: 1 AN: 29488

American (AMR) AF: 0.00 AC: 0 AN: 39152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24482

East Asian (EAS) AF: 0.00 AC: 0 AN: 33662

South Asian (SAS) AF: 0.00 AC: 0 AN: 80082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3840

European-Non Finnish (NFE) AF: 0.00000202 AC: 2 AN: 992152

Other (OTH) AF: 0.00 AC: 0 AN: 54258

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000109 AC: 1 AN: 91834 Hom.: 0 Cov.: 11 AF XY: 0.0000234 AC XY: 1 AN XY: 42736

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

African (AFR) AF: 0.0000409 AC: 1 AN: 24460

American (AMR) AF: 0.00 AC: 0 AN: 8242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2416

East Asian (EAS) AF: 0.00 AC: 0 AN: 2074

South Asian (SAS) AF: 0.00 AC: 0 AN: 1950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45670

Other (OTH) AF: 0.00 AC: 0 AN: 1044

⚠️ 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.

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	0.13
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.21	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.080	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.081
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.080	T
Polyphen		0.87	P
Vest4		0.12
MutPred		0.17		Gain of methylation at R391 (P = 0.069)
MVP		0.088
ClinPred		0.17	T
Varity_R		0.065
gMVP		0.0097
Mutation Taster		=98/2	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

hg19: chr9-70176814;