rs3739070

Variant names:

• chr2-238397627-A-C
• rs3739070
• NM_015650.4:c.1858A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-238397627-A-C
• chr2-238397627-A-G
• chr2-238397627-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015650.4(TRAF3IP1):​c.1858A>C​(p.Met620Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,607,770 control chromosomes in the GnomAD database, including 5,344 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M620I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.062 (386 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4958 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.126
• Publications: 45 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
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017504692).
• BP6: Variant 2-238397627-A-C is Benign according to our data. Variant chr2-238397627-A-C is described in ClinVar as Benign. ClinVar VariationId is 1166906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

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.1858A>C	p.Met620Leu	missense	Exon 16 of 17	NP_056465.2
	TRAF3IP1	NM_001139490.1		c.1660A>C	p.Met554Leu	missense	Exon 14 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.1858A>C	p.Met620Leu	missense	Exon 16 of 17	ENSP00000362424.4	Q8TDR0-1
	TRAF3IP1	ENST00000391993.7	TSL:1	c.1660A>C	p.Met554Leu	missense	Exon 14 of 15	ENSP00000375851.3	Q8TDR0-2
	TRAF3IP1	ENST00000935943.1		c.1762A>C	p.Met588Leu	missense	Exon 15 of 16	ENSP00000606002.1

Frequencies

GnomAD3 genomes AF: 0.0615 AC: 9313 AN: 151342 Hom.: 384 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0479

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0805

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0635 AC: 15763 AN: 248156 AF XY: 0.0645

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.0385

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.0790

Gnomad OTH exome AF: 0.0617

GnomAD4 exome AF: 0.0774 AC: 112720 AN: 1456310 Hom.: 4958 Cov.: 33 AF XY: 0.0763 AC XY: 55314 AN XY: 724508

African (AFR) AF: 0.0212 AC: 707 AN: 33406

American (AMR) AF: 0.0306 AC: 1368 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0503 AC: 1314 AN: 26100

East Asian (EAS) AF: 0.0321 AC: 1272 AN: 39668

South Asian (SAS) AF: 0.0422 AC: 3633 AN: 86182

European-Finnish (FIN) AF: 0.147 AC: 7643 AN: 52092

Middle Eastern (MID) AF: 0.0200 AC: 115 AN: 5760

European-Non Finnish (NFE) AF: 0.0835 AC: 92523 AN: 1108224

Other (OTH) AF: 0.0688 AC: 4145 AN: 60210

GnomAD4 genome AF: 0.0615 AC: 9322 AN: 151460 Hom.: 386 Cov.: 32 AF XY: 0.0625 AC XY: 4626 AN XY: 74008

African (AFR) AF: 0.0238 AC: 984 AN: 41356

American (AMR) AF: 0.0416 AC: 633 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0479 AC: 166 AN: 3466

East Asian (EAS) AF: 0.0456 AC: 234 AN: 5128

South Asian (SAS) AF: 0.0455 AC: 216 AN: 4746

European-Finnish (FIN) AF: 0.141 AC: 1484 AN: 10496

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0806 AC: 5456 AN: 67734

Other (OTH) AF: 0.0560 AC: 118 AN: 2108

Alfa AF: 0.0697 Hom.: 1718

Bravo AF: 0.0528

TwinsUK AF: 0.0928 AC: 344

ALSPAC AF: 0.0867 AC: 334

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.0776 AC: 667

ExAC AF: 0.0667 AC: 8093

Asia WGS AF: 0.0370 AC: 127 AN: 3418

EpiCase AF: 0.0712

EpiControl AF: 0.0733

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.58
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.13
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.052
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.098
MutPred		0.61		Loss of catalytic residue at M620 (P = 0.0267)
MPC		0.13
ClinPred		0.00022	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.048
Mutation Taster		=99/1	polymorphism (auto)

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: rs3739070; hg19: chr2-239306268; COSMIC: COSV64852869;