rs1214100414

Variant names:

• chr2-238320688-C-G
• rs1214100414
• NM_015650.4:c.26C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-238320688-C-G
• chr2-238320688-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015650.4(TRAF3IP1):​c.26C>G​(p.Thr9Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000079 in 1,266,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.27
• Publications: 0 publications found

Genes affected

TRAF3IP1 (HGNC:17861): (TRAF3 interacting protein 1) The protein encoded by this gene interacts with TNF receptor-associated factor 3, tethering it to cytoskeletal microtubules. The encoded protein is also an inhibitor of the innate type I IFN response. Defects in this gene are a cause of Senior-Loken syndrome 9. [provided by RefSeq, Mar 2017]

TRAF3IP1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Senior-Loken syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015650.4. 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
	TRAF3IP1	NM_015650.4	MANE Select	c.26C>G	p.Thr9Arg	missense	Exon 1 of 17	NP_056465.2
	TRAF3IP1	NM_001139490.1		c.26C>G	p.Thr9Arg	missense	Exon 1 of 15	NP_001132962.1	Q8TDR0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP1	ENST00000373327.5	TSL:1 MANE Select	c.26C>G	p.Thr9Arg	missense	Exon 1 of 17	ENSP00000362424.4	Q8TDR0-1
	TRAF3IP1	ENST00000391993.7	TSL:1	c.26C>G	p.Thr9Arg	missense	Exon 1 of 15	ENSP00000375851.3	Q8TDR0-2
	TRAF3IP1	ENST00000935943.1		c.26C>G	p.Thr9Arg	missense	Exon 1 of 16	ENSP00000606002.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.90e-7 AC: 1 AN: 1266292 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 624548

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25538

American (AMR) AF: 0.00 AC: 0 AN: 25126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20720

East Asian (EAS) AF: 0.00 AC: 0 AN: 25344

South Asian (SAS) AF: 0.00 AC: 0 AN: 67626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4698

European-Non Finnish (NFE) AF: 9.96e-7 AC: 1 AN: 1003716

Other (OTH) AF: 0.00 AC: 0 AN: 49804

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.52		Loss of phosphorylation at T9 (P = 0.0183)
MVP		0.53
MPC		0.56
ClinPred		1.0	D
GERP RS		3.4
PromoterAI		0.019	Neutral
Varity_R		0.94
gMVP		0.92
Mutation Taster		=8/92	disease causing

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: rs1214100414; hg19: chr2-239229329;