22-26499291-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012143.4(TFIP11):c.1142A>G(p.Glu381Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFIP11 NM_012143.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

Genes affected

TFIP11 (HGNC:17165): (tuftelin interacting protein 11) This gene encodes a protein component of the spliceosome that promotes the release of the lariat-intron during late-stage splicing through the recruitment of a pre-mRNA splicing factor called DEAH-box helicase 15. The encoded protein contains a G-patch domain, a hallmark of RNA-processing proteins, that binds DEAH-box helicase 15. This protein contains an atypical nuclear localization sequence as well as a nuclear speckle-targeting sequence, enabling it to localize to distinct speckled regions within the cell nucleus. Polymorphisms in this gene are associated with dental caries suggesting a role in amelogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3372739).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFIP11	NM_012143.4	c.1142A>G	p.Glu381Gly	missense_variant	9/15	ENST00000407690.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFIP11	ENST00000407690.6	c.1142A>G	p.Glu381Gly	missense_variant	9/15	1	NM_012143.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250710 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.1142A>G (p.E381G) alteration is located in exon 10 (coding exon 6) of the TFIP11 gene. This alteration results from a A to G substitution at nucleotide position 1142, causing the glutamic acid (E) at amino acid position 381 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;T;T;T
Eigen	Benign	0.036
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.74	T;.;.;.;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B
Vest4		0.61
MutPred		0.33		Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);
MVP		0.67
MPC		0.45
ClinPred		0.61	D
GERP RS		4.6
Varity_R		0.16
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1475526255; hg19: chr22-26895257;