NM_001369369.1:c.1425G>T

Variant names:

• chr17-28534996-G-T
• rs115771646
• NM_001369369.1:c.1425G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001369369.1(FOXN1):​c.1425G>T​(p.Pro475Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P475P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXN1 NM_001369369.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0370
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-28534996-G-T is Benign according to our data. Variant chr17-28534996-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1670163.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.037 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.1425G>T	p.Pro475Pro	synonymous_variant	Exon 8 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.1425G>T	p.Pro475Pro	synonymous_variant	Exon 8 of 9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.1425G>T	p.Pro475Pro	synonymous_variant	Exon 7 of 8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1195+69055C>A		intron_variant	Intron 7 of 7	1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.1425G>T	p.Pro475Pro	synonymous_variant	Exon 8 of 9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.61
CADD	Benign	0.99
DANN	Benign	0.79
PhyloP100		0.037

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs115771646; hg19: chr17-26862014;