9-97432124-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014290.3(TDRD7):c.449T>C(p.Val150Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,613,408 control chromosomes in the GnomAD database, including 197,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21754 hom., cov: 32)
  • Exomes 𝑓: 0.49 (175732 hom.)
• Consequence: TDRD7 NM_014290.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0420

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.607712E-5).
• BP6: Variant 9-97432124-T-C is Benign according to our data. Variant chr9-97432124-T-C is described in ClinVar as [Benign]. Clinvar id is 260383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-97432124-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRD7	NM_014290.3	c.449T>C	p.Val150Ala	missense_variant	4/17	ENST00000355295.5
TDRD7	NM_001302884.2	c.227T>C	p.Val76Ala	missense_variant	3/16
TDRD7	XM_047423111.1	c.449T>C	p.Val150Ala	missense_variant	4/17
TDRD7	XM_047423113.1	c.449T>C	p.Val150Ala	missense_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRD7	ENST00000355295.5	c.449T>C	p.Val150Ala	missense_variant	4/17	1	NM_014290.3	P1

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80702 AN: 151888 Hom.: 21712 Cov.: 32

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.508 AC: 127446 AN: 250900 Hom.: 32906 AF XY: 0.499 AC XY: 67674 AN XY: 135590

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.581

Gnomad ASJ exome AF: 0.478

Gnomad EAS exome AF: 0.561

Gnomad SAS exome AF: 0.437

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.487

GnomAD4 exome AF: 0.488 AC: 713659 AN: 1461402 Hom.: 175732 Cov.: 50 AF XY: 0.486 AC XY: 353347 AN XY: 727024

Gnomad4 AFR exome AF: 0.608

Gnomad4 AMR exome AF: 0.578

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.530

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome AF: 0.532 AC: 80796 AN: 152006 Hom.: 21754 Cov.: 32 AF XY: 0.532 AC XY: 39485 AN XY: 74276

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.472

Gnomad4 EAS AF: 0.560

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.522

Alfa AF: 0.496 Hom.: 46610

Bravo AF: 0.540

TwinsUK AF: 0.476 AC: 1765

ALSPAC AF: 0.487 AC: 1878

ESP6500AA AF: 0.605 AC: 2664

ESP6500EA AF: 0.475 AC: 4088

ExAC AF: 0.507 AC: 61557

Asia WGS AF: 0.512 AC: 1781 AN: 3476

EpiCase AF: 0.475

EpiControl AF: 0.479

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 36 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.0
Dann	Benign	0.50
DEOGEN2	Benign	0.084	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.000036	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.013
Sift	Benign	0.69	T
Sift4G	Benign	0.64	T
Polyphen		0.010	B
Vest4		0.0070
MPC		0.19
ClinPred		0.00087	T
GERP RS		1.0
Varity_R		0.015
gMVP		0.18

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: rs2045732; hg19: chr9-100194406; COSMIC: COSV62428817;