20-62859377-C-G

Variant names:

• chr20-62859377-C-G
• NM_006602.4:c.981G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006602.4(TCFL5):​c.981G>C​(p.Trp327Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,454,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TCFL5 NM_006602.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

Genes affected

TCFL5 (HGNC:11646): (transcription factor like 5) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in several processes, including negative regulation of transcription by RNA polymerase II; regulation of cell population proliferation; and spermatogenesis. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCFL5	NM_006602.4	c.981G>C	p.Trp327Cys	missense_variant	Exon 3 of 6	ENST00000335351.8	NP_006593.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCFL5	ENST00000335351.8	c.981G>C	p.Trp327Cys	missense_variant	Exon 3 of 6	1	NM_006602.4	ENSP00000334294.3
TCFL5	ENST00000217162.5	c.837G>C	p.Trp279Cys	missense_variant	Exon 3 of 6	1		ENSP00000217162.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454388 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722096

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.981G>C (p.W327C) alteration is located in exon 3 (coding exon 3) of the TCFL5 gene. This alteration results from a G to C substitution at nucleotide position 981, causing the tryptophan (W) at amino acid position 327 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.35
Sift	Benign	0.16	T;T
Sift4G	Benign	0.20	T;T
Polyphen		1.0	D;P
Vest4		0.86
MutPred		0.59		Gain of disorder (P = 0.017);.;
MVP		0.23
MPC		0.027
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.55
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-61490729;