NM_014290.3:c.231C>T

Variant names:

• chr9-97430956-C-T
• rs143579801
• NM_014290.3:c.231C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_014290.3(TDRD7):​c.231C>T​(p.Cys77Cys) 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
• Publications: 1 publications found

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]

TDRD7 Gene-Disease associations (from GenCC):

• cataract 36

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -12 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 VariationId is 539171.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014290.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD7	NM_014290.3	MANE Select	c.231C>T	p.Cys77Cys	synonymous	Exon 3 of 17	NP_055105.2	Q8NHU6-1
	TDRD7	NM_001302884.2		c.9C>T	p.Cys3Cys	synonymous	Exon 2 of 16	NP_001289813.1	Q8NHU6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD7	ENST00000355295.5	TSL:1 MANE Select	c.231C>T	p.Cys77Cys	synonymous	Exon 3 of 17	ENSP00000347444.4	Q8NHU6-1
	TDRD7	ENST00000861598.1		c.231C>T	p.Cys77Cys	synonymous	Exon 4 of 18	ENSP00000531657.1
	TDRD7	ENST00000861599.1		c.231C>T	p.Cys77Cys	synonymous	Exon 3 of 17	ENSP00000531658.1

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

GnomAD2 exomes AF: 0.00113 AC: 285 AN: 251112 AF XY: 0.00122

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 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

African (AFR) AF: 0.000209 AC: 7 AN: 33448

American (AMR) AF: 0.000537 AC: 24 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 128 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86254

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53420

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00229 AC: 2545 AN: 1111794

Other (OTH) AF: 0.00181 AC: 109 AN: 60376

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

African (AFR) AF: 0.000144 AC: 6 AN: 41560

American (AMR) AF: 0.000327 AC: 5 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00207 Hom.: 0

Bravo AF: 0.00119

EpiCase AF: 0.00185

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Cataract 36 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.71
PhyloP100		0.96
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

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