chr17-28534333-A-G

Variant names:

• chr17-28534333-A-G
• rs143844274
• NM_001369369.1:c.930A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP7 BS1

This summary comes from the ClinGen Evidence Repository: NM_001369369.1(FOXN1):c.930A>G (p.Thr310=) is a synonymous variant. SpliceAI predicts no impact to the splice consensus sequence (delta score 0.00) nor the creation of a new splice site (delta score<=0.01) and the nucleotide is not highly conserved (phyloP score -1.54) (BP4, BP7). The gnomADv2.1.1 PopMax filtering AF is 0.002017 based on 66/24964alleles in the African/African American population, which is above the >0.00141 threshold for BS1. In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BS1, BP4, and BP7 as specified by the ClinGen SCID VCEP FOXN1 subgroup. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8459411/MONDO:0011132/113

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: FOXN1 NM_001369369.1 splice_region, synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: -1.47
• 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 -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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.930A>G	p.Thr310Thr	splice_region synonymous	Exon 7 of 9	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.930A>G	p.Thr310Thr	splice_region synonymous	Exon 6 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.930A>G	p.Thr310Thr	splice_region synonymous	Exon 7 of 9	ENSP00000464645.1	O15353
	FOXN1	ENST00000226247.2	TSL:1	c.930A>G	p.Thr310Thr	splice_region synonymous	Exon 6 of 8	ENSP00000226247.2	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1195+69718T>C		intron	N/A	ENSP00000436369.2	Q96LW2-2

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251482 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461868 Hom.: 0 Cov.: 33 AF XY: 0.0000426 AC XY: 31 AN XY: 727230

African (AFR) AF: 0.00200 AC: 67 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 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: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.000132 AC: 8 AN: 60396

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74460

African (AFR) AF: 0.00289 AC: 120 AN: 41568

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000763

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (2)
-	-	1	FOXN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.037
DANN	Benign	0.43
PhyloP100		-1.5

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: rs143844274; hg19: chr17-26861351;