rs35240903

Variant names:

• chr17-28529108-T-C
• rs35240903
• NM_001369369.1:c.714T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001369369.1(FOXN1):​c.714T>C​(p.Gly238Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,614,094 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (105 hom.)
• Consequence: FOXN1 NM_001369369.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.710
• Publications: 1 publications found

Genes affected

FOXN1 (HGNC:12765): (forkhead box N1) Mutations in the winged-helix transcription factor gene at the nude locus in mice and rats produce the pleiotropic phenotype of hairlessness and athymia, resulting in a severely compromised immune system. This gene is orthologous to the mouse and rat genes and encodes a similar DNA-binding transcription factor that is thought to regulate keratin gene expression. A mutation in this gene has been correlated with T-cell immunodeficiency, the skin disorder congenital alopecia, and nail dystrophy. Alternative splicing in the 5' UTR of this gene has been observed. [provided by RefSeq, Jul 2008]

RSKR (HGNC:26314): (ribosomal protein S6 kinase related) Predicted to enable protein kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-28529108-T-C is Benign according to our data. Variant chr17-28529108-T-C is described in ClinVar as Benign. ClinVar VariationId is 322424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0678 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369369.1. 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
	FOXN1	NM_001369369.1	MANE Select	c.714T>C	p.Gly238Gly	synonymous	Exon 5 of 9	NP_001356298.1
	FOXN1	NM_003593.3		c.714T>C	p.Gly238Gly	synonymous	Exon 4 of 8	NP_003584.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXN1	ENST00000579795.6	TSL:1 MANE Select	c.714T>C	p.Gly238Gly	synonymous	Exon 5 of 9	ENSP00000464645.1
	FOXN1	ENST00000226247.2	TSL:1	c.714T>C	p.Gly238Gly	synonymous	Exon 4 of 8	ENSP00000226247.2
	RSKR	ENST00000481916.6	TSL:1	n.*1196-72999A>G		intron	N/A	ENSP00000436369.2

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3069 AN: 152104 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0697

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00587 AC: 1477 AN: 251460 AF XY: 0.00408

Gnomad AFR exome AF: 0.0774

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00226 AC: 3309 AN: 1461872 Hom.: 105 Cov.: 32 AF XY: 0.00198 AC XY: 1439 AN XY: 727238

African (AFR) AF: 0.0750 AC: 2510 AN: 33478

American (AMR) AF: 0.00470 AC: 210 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26136

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

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.000166 AC: 185 AN: 1111992

Other (OTH) AF: 0.00517 AC: 312 AN: 60396

GnomAD4 genome AF: 0.0203 AC: 3086 AN: 152222 Hom.: 93 Cov.: 32 AF XY: 0.0191 AC XY: 1425 AN XY: 74436

African (AFR) AF: 0.0699 AC: 2904 AN: 41532

American (AMR) AF: 0.00694 AC: 106 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68002

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0114 Hom.: 39

Bravo AF: 0.0235

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.60
DANN	Benign	0.55
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs35240903; hg19: chr17-26856126;