6-13294772-C-T

Variant names:

• chr6-13294772-C-T
• rs20499
• NM_001318809.2:c.*39+10290G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001318809.2(TBC1D7-LOC100130357):​c.*39+10290G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,242,554 control chromosomes in the GnomAD database, including 23,802 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2245 hom., cov: 33)
  • Exomes 𝑓: 0.19 (21557 hom.)
• Consequence: TBC1D7-LOC100130357 NM_001318809.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 9 publications found

Genes affected

TBC1D7-LOC100130357 (HGNC:):

TBC1D7 (HGNC:21066): (TBC1 domain family member 7) This gene encodes a member of the TBC-domain containing protein family. The encoded protein functions as a subunit of the tuberous sclerosis TSC1-TSC2 complex which plays a role in the regulation of cellular growth and differentiation. Mutations in this gene have been associated with autosomal recessive megalencephaly. Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between this locus and downstream LOC100130357. [provided by RefSeq, Jan 2016]

TBC1D7 Gene-Disease associations (from GenCC):

• macrocephaly/megalencephaly syndrome, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D7-LOC100130357	NM_001318809.2	c.*39+10290G>A		intron_variant	Intron 8 of 8		NP_001305738.1
TBC1D7-LOC100130357	NR_134872.2	n.712+24G>A		intron_variant	Intron 6 of 7
LOC100130357	NR_160971.1	n.318+24G>A		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D7	ENST00000606214.5	c.*39+10290G>A		intron_variant	Intron 7 of 7	5		ENSP00000475727.1
TBC1D7	ENST00000421203.6	n.*82+24G>A		intron_variant	Intron 6 of 7	2		ENSP00000401438.2
ENSG00000215022	ENST00000606150.5	n.318+24G>A		intron_variant	Intron 3 of 4	2
ENSG00000215022	ENST00000612479.1	n.140+24G>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25491 AN: 152122 Hom.: 2250 Cov.: 33

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.200 AC: 27715 AN: 138912 AF XY: 0.208

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.194 AC: 211373 AN: 1090312 Hom.: 21557 Cov.: 17 AF XY: 0.197 AC XY: 106075 AN XY: 537356

African (AFR) AF: 0.102 AC: 2381 AN: 23382

American (AMR) AF: 0.153 AC: 4320 AN: 28186

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 2751 AN: 15624

East Asian (EAS) AF: 0.267 AC: 3361 AN: 12576

South Asian (SAS) AF: 0.292 AC: 22000 AN: 75230

European-Finnish (FIN) AF: 0.153 AC: 2044 AN: 13338

Middle Eastern (MID) AF: 0.197 AC: 851 AN: 4326

European-Non Finnish (NFE) AF: 0.189 AC: 165777 AN: 877544

Other (OTH) AF: 0.197 AC: 7888 AN: 40106

GnomAD4 genome AF: 0.167 AC: 25491 AN: 152242 Hom.: 2245 Cov.: 33 AF XY: 0.169 AC XY: 12578 AN XY: 74436

African (AFR) AF: 0.114 AC: 4721 AN: 41550

American (AMR) AF: 0.155 AC: 2371 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 635 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1386 AN: 5178

South Asian (SAS) AF: 0.307 AC: 1478 AN: 4818

European-Finnish (FIN) AF: 0.165 AC: 1747 AN: 10598

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12618 AN: 68002

Other (OTH) AF: 0.161 AC: 340 AN: 2110

Alfa AF: 0.173 Hom.: 508

Bravo AF: 0.160

Asia WGS AF: 0.289 AC: 1003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.49
DANN	Benign	0.72
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs20499; hg19: chr6-13295004; COSMIC: COSV69720961; COSMIC: COSV69720961;