chr19-19194090-G-C

Variant names:

• chr19-19194090-G-C
• rs34282046
• NM_003721.4:c.144G>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.144G>C​(p.Glu48Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,614,068 control chromosomes in the GnomAD database, including 2,728 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (226 hom., cov: 31)
  • Exomes 𝑓: 0.056 (2502 hom.)
• Consequence: RFXANK NM_003721.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.118
• Publications: 24 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015137196).
• BP6: Variant 19-19194090-G-C is Benign according to our data. Variant chr19-19194090-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003721.4. 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
	RFXANK	NM_003721.4	MANE Select	c.144G>C	p.Glu48Asp	missense	Exon 3 of 10	NP_003712.1	O14593-1
	RFXANK	NM_001370238.1		c.144G>C	p.Glu48Asp	missense	Exon 2 of 10	NP_001357167.1
	RFXANK	NM_001370237.1		c.144G>C	p.Glu48Asp	missense	Exon 2 of 10	NP_001357166.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.144G>C	p.Glu48Asp	missense	Exon 3 of 10	ENSP00000305071.2	O14593-1
	RFXANK	ENST00000407360.7	TSL:1	c.144G>C	p.Glu48Asp	missense	Exon 2 of 9	ENSP00000384572.3	O14593-1
	RFXANK	ENST00000456252.7	TSL:1	c.144G>C	p.Glu48Asp	missense	Exon 3 of 9	ENSP00000409138.2	O14593-3

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6898 AN: 152106 Hom.: 219 Cov.: 31

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0899

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.0663

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0592

Gnomad OTH AF: 0.0579

GnomAD2 exomes AF: 0.0530 AC: 13332 AN: 251488 AF XY: 0.0529

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0954

Gnomad ASJ exome AF: 0.0509

Gnomad EAS exome AF: 0.0131

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0561 AC: 81975 AN: 1461844 Hom.: 2502 Cov.: 32 AF XY: 0.0564 AC XY: 41030 AN XY: 727234

African (AFR) AF: 0.0105 AC: 352 AN: 33480

American (AMR) AF: 0.0986 AC: 4409 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 1245 AN: 26136

East Asian (EAS) AF: 0.0280 AC: 1111 AN: 39700

South Asian (SAS) AF: 0.0709 AC: 6118 AN: 86258

European-Finnish (FIN) AF: 0.0230 AC: 1230 AN: 53418

Middle Eastern (MID) AF: 0.0352 AC: 203 AN: 5768

European-Non Finnish (NFE) AF: 0.0575 AC: 63920 AN: 1111964

Other (OTH) AF: 0.0561 AC: 3387 AN: 60396

GnomAD4 genome AF: 0.0454 AC: 6908 AN: 152224 Hom.: 226 Cov.: 31 AF XY: 0.0455 AC XY: 3386 AN XY: 74426

African (AFR) AF: 0.0119 AC: 495 AN: 41544

American (AMR) AF: 0.0908 AC: 1387 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3470

East Asian (EAS) AF: 0.0208 AC: 108 AN: 5180

South Asian (SAS) AF: 0.0662 AC: 319 AN: 4822

European-Finnish (FIN) AF: 0.0208 AC: 221 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0592 AC: 4024 AN: 68000

Other (OTH) AF: 0.0573 AC: 121 AN: 2112

Alfa AF: 0.0563 Hom.: 175

Bravo AF: 0.0489

TwinsUK AF: 0.0588 AC: 218

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0560 AC: 482

ExAC AF: 0.0506 AC: 6144

Asia WGS AF: 0.0460 AC: 158 AN: 3478

EpiCase AF: 0.0599

EpiControl AF: 0.0582

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	MHC class II deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.3
DANN	Benign	0.62
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.11	N
PhyloP100		-0.12
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.028
Sift	Benign	0.23	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.098		Loss of helix (P = 0.1706)
MPC		0.23
ClinPred		0.00018	T
GERP RS		0.43
PromoterAI		-0.0080	Neutral
Varity_R		0.046
gMVP		0.098
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: rs34282046; hg19: chr19-19304899; COSMIC: COSV50763572; COSMIC: COSV50763572;