NM_052945.4:c.229C>T

Variant names:

• chr22-41926239-G-A
• rs140820836
• NM_052945.4:c.229C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_052945.4(TNFRSF13C):​c.229C>T​(p.Leu77Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,563,654 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L77L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (31 hom.)
• Consequence: TNFRSF13C NM_052945.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.813
• Publications: 0 publications found

Genes affected

TNFRSF13C (HGNC:17755): (TNF receptor superfamily member 13C) B cell-activating factor (BAFF) enhances B-cell survival in vitro and is a regulator of the peripheral B-cell population. Overexpression of Baff in mice results in mature B-cell hyperplasia and symptoms of systemic lupus erythematosus (SLE). Also, some SLE patients have increased levels of BAFF in serum. Therefore, it has been proposed that abnormally high levels of BAFF may contribute to the pathogenesis of autoimmune diseases by enhancing the survival of autoreactive B cells. The protein encoded by this gene is a receptor for BAFF and is a type III transmembrane protein containing a single extracellular cysteine-rich domain. It is thought that this receptor is the principal receptor required for BAFF-mediated mature B-cell survival. [provided by RefSeq, Jul 2008]

TNFRSF13C Gene-Disease associations (from GenCC):

• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency, common variable, 4

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 22-41926239-G-A is Benign according to our data. Variant chr22-41926239-G-A is described in ClinVar as Benign. ClinVar VariationId is 487214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.813 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1615/152272) while in subpopulation AFR AF = 0.0379 (1577/41564). AF 95% confidence interval is 0.0364. There are 32 homozygotes in GnomAd4. There are 779 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052945.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13C	NM_052945.4	MANE Select	c.229C>T	p.Leu77Leu	synonymous	Exon 2 of 3	NP_443177.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13C	ENST00000291232.5	TSL:1 MANE Select	c.229C>T	p.Leu77Leu	synonymous	Exon 2 of 3	ENSP00000291232.3

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1610 AN: 152164 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00242 AC: 397 AN: 163878 AF XY: 0.00186

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.00105 AC: 1487 AN: 1411382 Hom.: 31 Cov.: 33 AF XY: 0.000927 AC XY: 648 AN XY: 698986

African (AFR) AF: 0.0395 AC: 1283 AN: 32478

American (AMR) AF: 0.000614 AC: 24 AN: 39100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.00 AC: 0 AN: 37608

South Asian (SAS) AF: 0.0000488 AC: 4 AN: 81992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39830

Middle Eastern (MID) AF: 0.000378 AC: 2 AN: 5288

European-Non Finnish (NFE) AF: 0.0000751 AC: 82 AN: 1091256

Other (OTH) AF: 0.00157 AC: 92 AN: 58574

GnomAD4 genome AF: 0.0106 AC: 1615 AN: 152272 Hom.: 32 Cov.: 32 AF XY: 0.0105 AC XY: 779 AN XY: 74448

African (AFR) AF: 0.0379 AC: 1577 AN: 41564

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.0116

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Immunodeficiency, common variable, 4 (3)
-	-	1	not provided (1)
-	-	1	TNFRSF13C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.8
DANN	Benign	0.83
PhyloP100		0.81
Mutation Taster		=100/0	polymorphism

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: rs140820836; hg19: chr22-42322243;