rs79003009

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
• Publications: 3 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]

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]

BORCS8 Gene-Disease associations (from GenCC):

• neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• inherited neurodegenerative disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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	ENST00000303088.9	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

African (AFR) AF: 0.00513 AC: 32 AN: 6232

American (AMR) AF: 0.0799 AC: 630 AN: 7886

Ashkenazi Jewish (ASJ) AF: 0.0422 AC: 279 AN: 6610

East Asian (EAS) AF: 0.109 AC: 1329 AN: 12208

South Asian (SAS) AF: 0.0421 AC: 959 AN: 22760

European-Finnish (FIN) AF: 0.0327 AC: 400 AN: 12240

Middle Eastern (MID) AF: 0.0406 AC: 39 AN: 960

European-Non Finnish (NFE) AF: 0.0301 AC: 3751 AN: 124426

Other (OTH) 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

African (AFR) AF: 0.00645 AC: 268 AN: 41578

American (AMR) AF: 0.0765 AC: 1170 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3472

East Asian (EAS) AF: 0.130 AC: 671 AN: 5160

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4824

European-Finnish (FIN) AF: 0.0335 AC: 356 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0342 AC: 2323 AN: 68008

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

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
PhyloP100		-0.80
PromoterAI		0.027	Neutral
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

Other links and lift over

dbSNP: rs79003009; hg19: chr19-19303284;