rs113406972

Variant names:

• chr19-19201701-G-A
• rs113406972
• NM_003721.4:c.765G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_003721.4(RFXANK):​c.765G>A​(p.Val255Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,614,064 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: RFXANK NM_003721.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.675
• Publications: 0 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]

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• BP6: Variant 19-19201701-G-A is Benign according to our data. Variant chr19-19201701-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328649.
• BP7: Synonymous conserved (PhyloP=0.675 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00162 (246/152310) while in subpopulation AFR AF = 0.00539 (224/41562). AF 95% confidence interval is 0.00481. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.765G>A	p.Val255Val	synonymous	Exon 10 of 10	NP_003712.1	O14593-1
	NR2C2AP	NM_176880.6	MANE Select	c.*224C>T		3_prime_UTR	Exon 5 of 5	NP_795361.1	Q86WQ0-1
	RFXANK	NM_001370238.1		c.840G>A	p.Val280Val	synonymous	Exon 10 of 10	NP_001357167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.765G>A	p.Val255Val	synonymous	Exon 10 of 10	ENSP00000305071.2	O14593-1
	RFXANK	ENST00000407360.7	TSL:1	c.765G>A	p.Val255Val	synonymous	Exon 9 of 9	ENSP00000384572.3	O14593-1
	RFXANK	ENST00000456252.7	TSL:1	c.699G>A	p.Val233Val	synonymous	Exon 9 of 9	ENSP00000409138.2	O14593-3

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000399 AC: 100 AN: 250678 AF XY: 0.000302

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461754 Hom.: 1 Cov.: 31 AF XY: 0.000168 AC XY: 122 AN XY: 727182

African (AFR) AF: 0.00621 AC: 208 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111988

Other (OTH) AF: 0.000397 AC: 24 AN: 60390

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74470

African (AFR) AF: 0.00539 AC: 224 AN: 41562

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000947 Hom.: 0

Bravo AF: 0.00194

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	MHC class II deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.79
PhyloP100		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113406972; hg19: chr19-19312510;