rs143579801

chr9-97430956-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_014290.3(TDRD7):c.231C>T(p.Cys77=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,613,818 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: TDRD7 NM_014290.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.961

Genes affected

TDRD7 (HGNC:30831): (tudor domain containing 7) The protein encoded by this gene belongs to the Tudor family of proteins. This protein contains conserved Tudor domains and LOTUS domains. It is a component of RNA granules, which function in RNA processing. Mutations in this gene have been associated with cataract formation in mouse and human. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 9-97430956-C-T is Benign according to our data. Variant chr9-97430956-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539171.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.961 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00124 (189/152254) while in subpopulation NFE AF= 0.00231 (157/68010). AF 95% confidence interval is 0.00201. There are 1 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRD7	NM_014290.3	c.231C>T	p.Cys77=	synonymous_variant	3/17	ENST00000355295.5
TDRD7	NM_001302884.2	c.9C>T	p.Cys3=	synonymous_variant	2/16
TDRD7	XM_047423111.1	c.231C>T	p.Cys77=	synonymous_variant	3/17
TDRD7	XM_047423113.1	c.231C>T	p.Cys77=	synonymous_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRD7	ENST00000355295.5	c.231C>T	p.Cys77=	synonymous_variant	3/17	1	NM_014290.3	P1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00113 AC: 285 AN: 251112 Hom.: 0 AF XY: 0.00122 AC XY: 166 AN XY: 135686

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00196 AC: 2860 AN: 1461564 Hom.: 5 Cov.: 32 AF XY: 0.00191 AC XY: 1390 AN XY: 727082

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74418

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00207 Hom.: 0

Bravo AF: 0.00119

EpiCase AF: 0.00185

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 36 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	15
Dann	Benign	0.71

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

Other links and lift over

dbSNP: rs143579801; hg19: chr9-100193238; COSMIC: COSV62428224;