22-26491530-C-T

Variant summary

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

The NM_001013694.3(SRRD):c.878C>T(p.Thr293Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SRRD
NM_001013694.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89

Variant links:

Genes affected

SRRD (HGNC:33910): (SRR1 domain containing) Predicted to be involved in microtubule-based process; regulation of circadian rhythm; and regulation of heme biosynthetic process. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SRRD links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRRD	NM_001013694.3 linkuse as main transcript	c.878C>T	p.Thr293Ile	missense_variant	7/7	ENST00000215917.11
TFIP11	NM_012143.4 linkuse as main transcript	c.*483G>A		3_prime_UTR_variant	15/15	ENST00000407690.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRRD	ENST00000215917.11 linkuse as main transcript	c.878C>T	p.Thr293Ile	missense_variant	7/7	1	NM_001013694.3	P1
TFIP11	ENST00000407690.6 linkuse as main transcript	c.*483G>A		3_prime_UTR_variant	15/15	1	NM_012143.4	P1	Q9UBB9-1
TFIP11	ENST00000619735.4 linkuse as main transcript	c.*483G>A		3_prime_UTR_variant	13/13	1		P1	Q9UBB9-1
SRRD	ENST00000471799.1 linkuse as main transcript	n.366C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000761

AC:

AN:

249546

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1461662

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000890

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000125

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.0000828

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.878C>T (p.T293I) alteration is located in exon 7 (coding exon 7) of the SRRD gene. This alteration results from a C to T substitution at nucleotide position 878, causing the threonine (T) at amino acid position 293 to be replaced by an isoleucine (I). 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.12

Cadd

Benign

Dann

Benign

0.93

DEOGEN2

Benign

0.22

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.046

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.79

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.26

Sift

Benign

0.068

Sift4G

Pathogenic

0.0

Polyphen

0.58

Vest4

0.55

MutPred

0.75

Gain of helix (P = 0.132);

MVP

0.51

MPC

0.061

ClinPred

0.57

GERP RS

4.3

Varity_R

0.28

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over