22-26499121-C-T

Position:

• chr22-26499121-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012143.4(TFIP11):​c.1312G>A​(p.Glu438Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: 1.78

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]

TFIP11 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1640333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFIP11	NM_012143.4	c.1312G>A	p.Glu438Lys	missense_variant	9/15	ENST00000407690.6	NP_036275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFIP11	ENST00000407690.6	c.1312G>A	p.Glu438Lys	missense_variant	9/15	1	NM_012143.4	ENSP00000384421.1

Frequencies

GnomAD3 genomes Cov.: 32

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

Aug 12, 2022

The c.1312G>A (p.E438K) alteration is located in exon 10 (coding exon 6) of the TFIP11 gene. This alteration results from a G to A substitution at nucleotide position 1312, causing the glutamic acid (E) at amino acid position 438 to be replaced by a lysine (K). 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	0.080
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;T;T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;.;.;.;.
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L;L;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.47	.;N;N;N;N
REVEL	Benign	0.086
Sift	Benign	0.40	.;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T
Polyphen		0.011	B;B;B;B;B
Vest4		0.21
MutPred		0.53		Gain of methylation at E438 (P = 0.0122);Gain of methylation at E438 (P = 0.0122);Gain of methylation at E438 (P = 0.0122);Gain of methylation at E438 (P = 0.0122);Gain of methylation at E438 (P = 0.0122);
MVP		0.65
MPC		0.44
ClinPred		0.29	T
GERP RS		5.2
Varity_R		0.084
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs1922424230; hg19: chr22-26895087;