chr1-1211957-C-T

Position:

• chr1-1211957-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003327.4(TNFRSF4):​c.619G>A​(p.Val207Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,578,222 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: TNFRSF4 NM_003327.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.801

Genes affected

TNFRSF4 (HGNC:11918): (TNF receptor superfamily member 4) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009646505).
• BP6: Variant 1-1211957-C-T is Benign according to our data. Variant chr1-1211957-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474797.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-1211957-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF4	NM_003327.4	c.619G>A	p.Val207Met	missense_variant	5/7	ENST00000379236.4	NP_003318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF4	ENST00000379236.4	c.619G>A	p.Val207Met	missense_variant	5/7	1	NM_003327.4	ENSP00000368538	P1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000845 AC: 170 AN: 201084 Hom.: 2 AF XY: 0.000729 AC XY: 81 AN XY: 111158

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000634

Gnomad SAS exome AF: 0.000379

Gnomad FIN exome AF: 0.000489

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000404

GnomAD4 exome AF: 0.00167 AC: 2379 AN: 1425984 Hom.: 4 Cov.: 31 AF XY: 0.00158 AC XY: 1120 AN XY: 706722

Gnomad4 AFR exome AF: 0.000338

Gnomad4 AMR exome AF: 0.000310

Gnomad4 ASJ exome AF: 0.0000404

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000690

Gnomad4 FIN exome AF: 0.000855

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74434

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00150 Hom.: 2

Bravo AF: 0.000903

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00148 AC: 12

ExAC AF: 0.000768 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Combined immunodeficiency due to OX40 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.81
DANN	Benign	0.93
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Benign	0.093	T
Polyphen		0.86	P
Vest4		0.11
MVP		0.32
MPC		0.15
ClinPred		0.0094	T
GERP RS		-4.3
Varity_R		0.035
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs201461846; hg19: chr1-1147337;