NM_001369369.1:c.9G>A

Variant names:

• chr17-28523978-G-A
• rs146390262
• NM_001369369.1:c.9G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001369369.1(FOXN1):​c.9G>A​(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,612,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: FOXN1 NM_001369369.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36

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

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-28523978-G-A is Benign according to our data. Variant chr17-28523978-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 468555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00273 (415/152146) while in subpopulation AFR AF= 0.00925 (384/41508). AF 95% confidence interval is 0.00849. There are 0 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.9G>A	p.Ser3Ser	synonymous_variant	Exon 2 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.9G>A	p.Ser3Ser	synonymous_variant	Exon 2 of 9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.9G>A	p.Ser3Ser	synonymous_variant	Exon 1 of 8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1196-67869C>T		intron_variant	Intron 7 of 7	1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.9G>A	p.Ser3Ser	synonymous_variant	Exon 2 of 9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00925

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000810 AC: 200 AN: 247034 Hom.: 0 AF XY: 0.000632 AC XY: 85 AN XY: 134554

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1460408 Hom.: 1 Cov.: 35 AF XY: 0.000234 AC XY: 170 AN XY: 726532

Gnomad4 AFR exome AF: 0.00858

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00273 AC: 415 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74374

Gnomad4 AFR AF: 0.00925

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.00325

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 21, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

T-cell immunodeficiency, congenital alopecia, and nail dystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs146390262; hg19: chr17-26850996;