rs2071587

Variant names:

• chr17-28524584-C-T
• rs2071587
• NM_001369369.1:c.205C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_001369369.1(FOXN1):c.205C>T is predicted to cause an arginine to cysteine substitution at amino acid position 69. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. The variant has a gnomAD popmax filtering allele frequency of 0.2496 based upon the Latino population, which is greater than 0.00447 and thus meets BA1. Additionally, the in-silico meta predictor REVEL suggests the variant has no effect on gene function with a score of 0.277, which is less than 0.290 and thus meets BP4. The variant is associated with the following publication: PMID:18006695. In summary, this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP4 and BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8459177/MONDO:0011132/113

• Frequency:
  • Genomes: 𝑓 0.081 (772 hom., cov: 33)
  • Exomes 𝑓: 0.090 (7268 hom.)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Benign reviewed by expert panel B:8 O:1
• Conservation: PhyloP100: 3.08
• Publications: 27 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

Specifications for FOXN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.205C>T	p.Arg69Cys	missense	Exon 3 of 9	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.205C>T	p.Arg69Cys	missense	Exon 2 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.205C>T	p.Arg69Cys	missense	Exon 3 of 9	ENSP00000464645.1	O15353
	FOXN1	ENST00000226247.2	TSL:1	c.205C>T	p.Arg69Cys	missense	Exon 2 of 8	ENSP00000226247.2	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-68475G>A		intron	N/A	ENSP00000436369.2	Q96LW2-2

Frequencies

GnomAD3 genomes AF: 0.0814 AC: 12381 AN: 152154 Hom.: 768 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.0722

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0941

GnomAD2 exomes AF: 0.110 AC: 27541 AN: 250372 AF XY: 0.104

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.0966

Gnomad NFE exome AF: 0.0814

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.0899 AC: 131401 AN: 1461270 Hom.: 7268 Cov.: 35 AF XY: 0.0883 AC XY: 64167 AN XY: 726972

African (AFR) AF: 0.0169 AC: 565 AN: 33478

American (AMR) AF: 0.249 AC: 11120 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 1577 AN: 26136

East Asian (EAS) AF: 0.220 AC: 8736 AN: 39698

South Asian (SAS) AF: 0.0721 AC: 6218 AN: 86254

European-Finnish (FIN) AF: 0.0934 AC: 4940 AN: 52902

Middle Eastern (MID) AF: 0.0567 AC: 327 AN: 5766

European-Non Finnish (NFE) AF: 0.0832 AC: 92490 AN: 1111924

Other (OTH) AF: 0.0899 AC: 5428 AN: 60392

GnomAD4 genome AF: 0.0814 AC: 12391 AN: 152272 Hom.: 772 Cov.: 33 AF XY: 0.0853 AC XY: 6353 AN XY: 74458

African (AFR) AF: 0.0218 AC: 907 AN: 41576

American (AMR) AF: 0.188 AC: 2883 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0665 AC: 231 AN: 3472

East Asian (EAS) AF: 0.202 AC: 1039 AN: 5148

South Asian (SAS) AF: 0.0714 AC: 345 AN: 4830

European-Finnish (FIN) AF: 0.102 AC: 1085 AN: 10616

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0825 AC: 5612 AN: 68006

Other (OTH) AF: 0.0931 AC: 197 AN: 2116

Alfa AF: 0.0869 Hom.: 1873

Bravo AF: 0.0862

TwinsUK AF: 0.0763 AC: 283

ALSPAC AF: 0.0804 AC: 310

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.0759 AC: 653

ExAC AF: 0.101 AC: 12278

Asia WGS AF: 0.101 AC: 350 AN: 3478

EpiCase AF: 0.0817

EpiControl AF: 0.0793

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (3)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.80	N
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.078	T
Polyphen		0.021	B
Vest4		0.059
MPC		0.20
ClinPred		0.12	T
GERP RS		3.3
Varity_R		0.19
gMVP		0.27
Mutation Taster		=95/5	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: rs2071587; hg19: chr17-26851602; COSMIC: COSV56880923;