19-19192475-C-T

Variant names:

• chr19-19192475-C-T
• rs79003009
• NM_003721.4:c.-229C>T

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.-229C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 357,878 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (162 hom., cov: 32)
  • Exomes 𝑓: 0.038 (257 hom.)
• Consequence: RFXANK NM_003721.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.797

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]

BORCS8 (HGNC:37247): (BLOC-1 related complex subunit 8) Involved in heart development. Part of BORC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-19192475-C-T is Benign according to our data. Variant chr19-19192475-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.-229C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000303088.9	NP_003712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088	c.-229C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_003721.4	ENSP00000305071.2

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5293 AN: 152156 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.00646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0547

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0384 AC: 7893 AN: 205604 Hom.: 257 Cov.: 0 AF XY: 0.0387 AC XY: 4185 AN XY: 108142

Gnomad4 AFR exome AF: 0.00513 AC: 32 AN: 6232

Gnomad4 AMR exome AF: 0.0799 AC: 630 AN: 7886

Gnomad4 ASJ exome AF: 0.0422 AC: 279 AN: 6610

Gnomad4 EAS exome AF: 0.109 AC: 1329 AN: 12208

Gnomad4 SAS exome AF: 0.0421 AC: 959 AN: 22760

Gnomad4 FIN exome AF: 0.0327 AC: 400 AN: 12240

Gnomad4 NFE exome AF: 0.0301 AC: 3751 AN: 124426

Gnomad4 Remaining exome AF: 0.0386 AC: 474 AN: 12282

GnomAD4 genome AF: 0.0348 AC: 5297 AN: 152274 Hom.: 162 Cov.: 32 AF XY: 0.0360 AC XY: 2682 AN XY: 74458

Gnomad4 AFR AF: 0.00645 AC: 0.00644572 AN: 0.00644572

Gnomad4 AMR AF: 0.0765 AC: 0.0765206 AN: 0.0765206

Gnomad4 ASJ AF: 0.0493 AC: 0.0492512 AN: 0.0492512

Gnomad4 EAS AF: 0.130 AC: 0.130039 AN: 0.130039

Gnomad4 SAS AF: 0.0551 AC: 0.055141 AN: 0.055141

Gnomad4 FIN AF: 0.0335 AC: 0.0335217 AN: 0.0335217

Gnomad4 NFE AF: 0.0342 AC: 0.0341577 AN: 0.0341577

Gnomad4 OTH AF: 0.0307 AC: 0.0307183 AN: 0.0307183

Alfa AF: 0.0124 Hom.: 1

Bravo AF: 0.0362

Asia WGS AF: 0.0890 AC: 307 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	2.2
DANN	Benign	0.89
Mutation Taster		=281/19	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

Publications

LitVar

Other links and lift over

dbSNP: rs79003009; hg19: chr19-19303284;