20-31844876-C-G

Variant names:

• chr20-31844876-C-G
• rs146664606
• NM_004118.4:c.667G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004118.4(FOXS1):​c.667G>C​(p.Gly223Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. G223S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FOXS1 NM_004118.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.276
• Publications: 3 publications found

Genes affected

FOXS1 (HGNC:3735): (forkhead box S1) The forkhead family of transcription factors belongs to the winged helix class of DNA-binding proteins. The protein encoded by this intronless gene contains a forkhead domain and is found predominantly in aorta and kidney. The function of the encoded protein is unknown. [provided by RefSeq, Jul 2008]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06642434).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004118.4. 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
	FOXS1	NM_004118.4	MANE Select	c.667G>C	p.Gly223Arg	missense	Exon 1 of 1	NP_004109.1	O43638

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXS1	ENST00000375978.5	TSL:6 MANE Select	c.667G>C	p.Gly223Arg	missense	Exon 1 of 1	ENSP00000365145.3	O43638

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251300 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000631 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.5
DANN	Benign	0.62
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.28
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.17	T
Polyphen		0.0050	B
Vest4		0.13
MutPred		0.23		Loss of glycosylation at S225 (P = 0.0592)
MVP		0.43
MPC		0.57
ClinPred		0.073	T
GERP RS		1.3
Varity_R		0.10
gMVP		0.25
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146664606; hg19: chr20-30432679;