2-238320704-G-A

Variant names:

• chr2-238320704-G-A
• rs766609697
• NM_015650.4:c.42G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_015650.4(TRAF3IP1):​c.42G>A​(p.Gly14Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000776 in 1,288,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G14G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: TRAF3IP1 NM_015650.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.221
• 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):

• Senior-Loken syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP7: Synonymous conserved (PhyloP=-0.221 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4	c.42G>A	p.Gly14Gly	synonymous_variant	Exon 1 of 17	ENST00000373327.5	NP_056465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF3IP1	ENST00000373327.5	c.42G>A	p.Gly14Gly	synonymous_variant	Exon 1 of 17	1	NM_015650.4	ENSP00000362424.4
TRAF3IP1	ENST00000391993.7	c.42G>A	p.Gly14Gly	synonymous_variant	Exon 1 of 15	1		ENSP00000375851.3
TRAF3IP1	ENST00000409739.2	n.42G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000386648.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.76e-7 AC: 1 AN: 1288716 Hom.: 0 Cov.: 30 AF XY: 0.00000157 AC XY: 1 AN XY: 635838

⚠️ 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: 25988

American (AMR) AF: 0.00 AC: 0 AN: 26428

Ashkenazi Jewish (ASJ) AF: 0.0000465 AC: 1 AN: 21508

East Asian (EAS) AF: 0.00 AC: 0 AN: 26290

South Asian (SAS) AF: 0.00 AC: 0 AN: 70544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4996

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1016836

Other (OTH) AF: 0.00 AC: 0 AN: 51138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		-0.22
PromoterAI		-0.0052	Neutral
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: rs766609697; hg19: chr2-239229345;