rs61737072

Variant names:

• chr21-44293100-T-C
• rs61737072
• NM_000383.4:c.1203T>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_000383.4(AIRE):​c.1203T>C​(p.Pro401Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00856 in 1,609,130 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (587 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (453 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.51
• Publications: 3 publications found

Genes affected

AIRE (HGNC:360): (autoimmune regulator) This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). [provided by RefSeq, Jun 2012]

AIRE Gene-Disease associations (from GenCC):

• autoimmune polyendocrine syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 21-44293100-T-C is Benign according to our data. Variant chr21-44293100-T-C is described in ClinVar as Benign. ClinVar VariationId is 35657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000383.4. 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
	AIRE	NM_000383.4	MANE Select	c.1203T>C	p.Pro401Pro	synonymous	Exon 10 of 14	NP_000374.1	O43918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1203T>C	p.Pro401Pro	synonymous	Exon 10 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.664T>C		non_coding_transcript_exon	Exon 3 of 7
	AIRE	ENST00000966178.1		c.1200T>C	p.Pro400Pro	synonymous	Exon 10 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7030 AN: 152094 Hom.: 587 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0118 AC: 2829 AN: 240148 AF XY: 0.00852

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000490

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00432

GnomAD4 exome AF: 0.00462 AC: 6734 AN: 1456918 Hom.: 453 Cov.: 34 AF XY: 0.00388 AC XY: 2808 AN XY: 724510

African (AFR) AF: 0.162 AC: 5401 AN: 33416

American (AMR) AF: 0.00942 AC: 417 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39582

South Asian (SAS) AF: 0.000210 AC: 18 AN: 85672

European-Finnish (FIN) AF: 0.000194 AC: 10 AN: 51640

Middle Eastern (MID) AF: 0.00599 AC: 34 AN: 5678

European-Non Finnish (NFE) AF: 0.000199 AC: 221 AN: 1110584

Other (OTH) AF: 0.0105 AC: 632 AN: 60148

GnomAD4 genome AF: 0.0463 AC: 7042 AN: 152212 Hom.: 587 Cov.: 32 AF XY: 0.0452 AC XY: 3363 AN XY: 74444

African (AFR) AF: 0.159 AC: 6621 AN: 41512

American (AMR) AF: 0.0198 AC: 303 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 67976

Other (OTH) AF: 0.0332 AC: 70 AN: 2110

Alfa AF: 0.0219 Hom.: 117

Bravo AF: 0.0530

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Polyglandular autoimmune syndrome, type 1 (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.96
DANN	Benign	0.44
PhyloP100		-2.5
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: rs61737072; hg19: chr21-45712983;