9-65283266-C-T

Variant names:

• chr9-65283266-C-T
• rs1447725837
• NM_001126334.1:c.1112G>A

Variant summary

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

The NM_001126334.1(FOXD4L5):​c.1112G>A​(p.Cys371Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. C371S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000067 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L5 NM_001126334.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.224
• 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=0.10814586).

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.1112G>A	p.Cys371Tyr	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.1112G>A	p.Cys371Tyr	missense	Exon 1 of 1	ENSP00000366637.1	Q5VV16

Frequencies

GnomAD3 genomes AF: 0.000100 AC: 13 AN: 129742 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

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: 0.000210

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000673 AC: 98 AN: 1455572 Hom.: 0 Cov.: 35 AF XY: 0.0000539 AC XY: 39 AN XY: 723410

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

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39264

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.0000848 AC: 94 AN: 1108730

Other (OTH) AF: 0.0000667 AC: 4 AN: 60012

⚠️ 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: 0.000100 AC: 13 AN: 129742 Hom.: 0 Cov.: 20 AF XY: 0.0000644 AC XY: 4 AN XY: 62106

African (AFR) AF: 0.00 AC: 0 AN: 35150

American (AMR) AF: 0.00 AC: 0 AN: 12396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3250

East Asian (EAS) AF: 0.00 AC: 0 AN: 3206

South Asian (SAS) AF: 0.00 AC: 0 AN: 3230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.000210 AC: 13 AN: 62002

Other (OTH) AF: 0.00 AC: 0 AN: 1608

Alfa AF: 0.00 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	0.12
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.22
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.37	T
Polyphen		0.70	P
Vest4		0.15
MutPred		0.32		Loss of ubiquitination at K373 (P = 0.0431)
MVP		0.25
ClinPred		0.16	T
GERP RS		1.1
Varity_R		0.64
gMVP		0.076
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: rs1447725837; hg19: chr9-70176872;