19-19201728-T-C

Variant names:

• chr19-19201728-T-C
• rs73922832
• NM_003721.4:c.*9T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003721.4(RFXANK):​c.*9T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,613,872 control chromosomes in the GnomAD database, including 388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (199 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (189 hom.)
• Consequence: RFXANK NM_003721.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.06

Genes affected

RFXANK (HGNC:9987): (regulatory factor X associated ankyrin containing protein) Major histocompatibility (MHC) class II molecules are transmembrane proteins that have a central role in development and control of the immune system. The protein encoded by this gene, along with regulatory factor X-associated protein and regulatory factor-5, forms a complex that binds to the X box motif of certain MHC class II gene promoters and activates their transcription. Once bound to the promoter, this complex associates with the non-DNA-binding factor MHC class II transactivator, which controls the cell type specificity and inducibility of MHC class II gene expression. This protein contains ankyrin repeats involved in protein-protein interactions. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group B. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2013]

NR2C2AP (HGNC:30763): (nuclear receptor 2C2 associated protein) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-19201728-T-C is Benign according to our data. Variant chr19-19201728-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 328650.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.*9T>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000303088.9	NP_003712.1
NR2C2AP	NM_176880.6	c.*197A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000331552.12	NP_795361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9	c.*9T>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_003721.4	ENSP00000305071.2
NR2C2AP	ENST00000331552	c.*197A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_176880.6	ENSP00000332823.6
NR2C2AP	ENST00000420605.7	c.415-165A>G		intron_variant	Intron 5 of 5	2		ENSP00000402756.1

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4212 AN: 152178 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.0963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00981

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00761 AC: 1902 AN: 249928 Hom.: 88 AF XY: 0.00560 AC XY: 757 AN XY: 135262

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0000936

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00300 AC: 4390 AN: 1461576 Hom.: 189 Cov.: 31 AF XY: 0.00260 AC XY: 1891 AN XY: 727112

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.00566

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00639

GnomAD4 genome AF: 0.0277 AC: 4218 AN: 152296 Hom.: 199 Cov.: 32 AF XY: 0.0260 AC XY: 1938 AN XY: 74476

Gnomad4 AFR AF: 0.0962

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0127 Hom.: 47

Bravo AF: 0.0316

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

RFXANK-related disorder Benign:1

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

MHC class II deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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	-0.87
CADD	Benign	0.023
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs73922832; hg19: chr19-19312537;