rs9622

Variant names:

• chr21-32578758-T-C
• rs9622
• NM_144659.7:c.434A>G

Variant summary

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

The NM_144659.7(TCP10L):​c.434A>G​(p.His145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,614,034 control chromosomes in the GnomAD database, including 28,739 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3092 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25647 hom.)
• Consequence: TCP10L NM_144659.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 24 publications found

Genes affected

TCP10L (HGNC:11657): (t-complex 10 like) Enables several functions, including identical protein binding activity; protein self-association; and transcription corepressor activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CFAP298-TCP10L (HGNC:54636): (CFAP298-TCP10L readthrough) This locus represents naturally occurring readthrough transcription between the neighboring chromosome 21 open reading frame 59 (C21orf59) and TCP10L (t-complex 10 like) genes on chromosome 21. Readthrough transcripts may encode a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004184574).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCP10L	NM_144659.7	c.434A>G	p.His145Arg	missense_variant	Exon 4 of 5	ENST00000300258.8	NP_653260.1
CFAP298-TCP10L	NM_001350338.2	c.956A>G	p.His319Arg	missense_variant	Exon 7 of 8		NP_001337267.1
CFAP298-TCP10L	NR_146638.2	n.1090A>G		non_coding_transcript_exon_variant	Exon 7 of 11
CFAP298-TCP10L	NR_146639.2	n.1090A>G		non_coding_transcript_exon_variant	Exon 7 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCP10L	ENST00000300258.8	c.434A>G	p.His145Arg	missense_variant	Exon 4 of 5	1	NM_144659.7	ENSP00000300258.3
CFAP298-TCP10L	ENST00000673807.1	c.956A>G	p.His319Arg	missense_variant	Exon 7 of 8			ENSP00000501088.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30388 AN: 152042 Hom.: 3077 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.206 AC: 51849 AN: 251456 AF XY: 0.207

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.184 AC: 269502 AN: 1461874 Hom.: 25647 Cov.: 33 AF XY: 0.186 AC XY: 135019 AN XY: 727236

African (AFR) AF: 0.204 AC: 6832 AN: 33480

American (AMR) AF: 0.203 AC: 9088 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 8423 AN: 26136

East Asian (EAS) AF: 0.309 AC: 12251 AN: 39698

South Asian (SAS) AF: 0.215 AC: 18541 AN: 86252

European-Finnish (FIN) AF: 0.225 AC: 11993 AN: 53420

Middle Eastern (MID) AF: 0.196 AC: 1133 AN: 5768

European-Non Finnish (NFE) AF: 0.170 AC: 189497 AN: 1112002

Other (OTH) AF: 0.194 AC: 11744 AN: 60394

GnomAD4 genome AF: 0.200 AC: 30437 AN: 152160 Hom.: 3092 Cov.: 32 AF XY: 0.204 AC XY: 15153 AN XY: 74374

African (AFR) AF: 0.206 AC: 8546 AN: 41504

American (AMR) AF: 0.194 AC: 2971 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3466

East Asian (EAS) AF: 0.289 AC: 1497 AN: 5172

South Asian (SAS) AF: 0.222 AC: 1070 AN: 4814

European-Finnish (FIN) AF: 0.223 AC: 2361 AN: 10598

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12243 AN: 67998

Other (OTH) AF: 0.214 AC: 451 AN: 2112

Alfa AF: 0.191 Hom.: 3519

Bravo AF: 0.198

TwinsUK AF: 0.172 AC: 636

ALSPAC AF: 0.164 AC: 632

ESP6500AA AF: 0.201 AC: 886

ESP6500EA AF: 0.182 AC: 1564

ExAC AF: 0.204 AC: 24754

Asia WGS AF: 0.255 AC: 885 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.185

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.019
DANN	Benign	0.56
DEOGEN2	Benign	0.00051	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00012	N
LIST_S2	Benign	0.30	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	N;.;.
PhyloP100		-1.1
PROVEAN	Benign	0.36	N;.;.
REVEL	Benign	0.025
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.018
MPC		0.074
ClinPred		0.000029	T
GERP RS		0.46
Varity_R		0.042
gMVP		0.027
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9622; hg19: chr21-33951068; COSMIC: COSV55829450; COSMIC: COSV55829450;