rs752772495

Variant names:

• chr2-238320751-C-A
• rs752772495
• NM_015650.4:c.89C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-238320751-C-A
• chr2-238320751-C-G
• chr2-238320751-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.89C>A​(p.Pro30His) variant causes a missense change. The variant allele was found at a frequency of 0.00000155 in 1,289,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.66
• 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, 0.762

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.89C>A	p.Pro30His	missense	Exon 1 of 17	NP_056465.2
	TRAF3IP1	NM_001139490.1		c.89C>A	p.Pro30His	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.89C>A	p.Pro30His	missense	Exon 1 of 17	ENSP00000362424.4	Q8TDR0-1
	TRAF3IP1	ENST00000391993.7	TSL:1	c.89C>A	p.Pro30His	missense	Exon 1 of 15	ENSP00000375851.3	Q8TDR0-2
	TRAF3IP1	ENST00000935943.1		c.89C>A	p.Pro30His	missense	Exon 1 of 16	ENSP00000606002.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1289282 Hom.: 0 Cov.: 33 AF XY: 0.00000157 AC XY: 1 AN XY: 636156

⚠️ 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: 25912

American (AMR) AF: 0.00 AC: 0 AN: 26448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21424

East Asian (EAS) AF: 0.00 AC: 0 AN: 26264

South Asian (SAS) AF: 0.00 AC: 0 AN: 70894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5134

European-Non Finnish (NFE) AF: 0.00000197 AC: 2 AN: 1016900

Other (OTH) AF: 0.00 AC: 0 AN: 51194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.46		Loss of catalytic residue at P30 (P = 8e-04)
MVP		0.50
MPC		0.64
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.74
Mutation Taster		=9/91	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: rs752772495; hg19: chr2-239229392;