NM_003721.4:c.-116T>C

Variant names:

• chr19-19192993-T-C
• rs1050483
• NM_003721.4:c.-116T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003721.4(RFXANK):​c.-116T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,234 control chromosomes in the GnomAD database, including 2,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2790 hom., cov: 32)
  • Exomes 𝑓: 0.15 (1 hom.)
• Consequence: RFXANK NM_003721.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06
• Publications: 14 publications found

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]

RFXANK Gene-Disease associations (from GenCC):

• MHC class II deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-19192993-T-C is Benign according to our data. Variant chr19-19192993-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 328639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.-116T>C		5_prime_UTR_variant	Exon 2 of 10	ENST00000303088.9	NP_003712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9	c.-116T>C		5_prime_UTR_variant	Exon 2 of 10	1	NM_003721.4	ENSP00000305071.2

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26548 AN: 152006 Hom.: 2775 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.145 AC: 16 AN: 110 Hom.: 1 Cov.: 0 AF XY: 0.125 AC XY: 10 AN XY: 80

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.357 AC: 5 AN: 14

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0976 AC: 8 AN: 82

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.175 AC: 26596 AN: 152124 Hom.: 2790 Cov.: 32 AF XY: 0.175 AC XY: 13008 AN XY: 74370

African (AFR) AF: 0.229 AC: 9523 AN: 41508

American (AMR) AF: 0.238 AC: 3632 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3468

East Asian (EAS) AF: 0.393 AC: 2020 AN: 5144

South Asian (SAS) AF: 0.227 AC: 1096 AN: 4822

European-Finnish (FIN) AF: 0.0695 AC: 736 AN: 10596

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8653 AN: 67992

Other (OTH) AF: 0.158 AC: 334 AN: 2114

Alfa AF: 0.144 Hom.: 2958

Bravo AF: 0.188

Asia WGS AF: 0.285 AC: 989 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.81
CADD	Benign	5.2
DANN	Benign	0.41
PhyloP100		-1.1
PromoterAI		0.079	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs1050483; hg19: chr19-19303802;