X-101278103-C-A

Variant names:

• chrX-101278103-C-A
• rs768889307
• NM_001168474.2:c.523G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001168474.2(TAF7L):​c.523G>T​(p.Val175Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,096,899 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V175M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: TAF7L NM_001168474.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37
• Publications: 2 publications found

Genes affected

TAF7L (HGNC:11548): (TATA-box binding protein associated factor 7 like) This gene is similar to a mouse gene that encodes a TATA box binding protein-associated factor, and shows testis-specific expression. The encoded protein could be a spermatogenesis-specific component of the DNA-binding general transcription factor complex TFIID. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168474.2. 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
	TAF7L	NM_001168474.2	MANE Select	c.523G>T	p.Val175Leu	missense	Exon 8 of 13	NP_001161946.1	Q5H9L4-2
	TAF7L	NM_024885.4		c.781G>T	p.Val261Leu	missense	Exon 8 of 13	NP_079161.3	Q5H9L4-1
	TAF7L	NM_001410720.1		c.523G>T	p.Val175Leu	missense	Exon 8 of 12	NP_001397649.1	Q5H9L4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF7L	ENST00000356784.2	TSL:1 MANE Select	c.523G>T	p.Val175Leu	missense	Exon 8 of 13	ENSP00000349235.1	Q5H9L4-2
	TAF7L	ENST00000372907.7	TSL:1	c.781G>T	p.Val261Leu	missense	Exon 8 of 13	ENSP00000361998.3	Q5H9L4-1
	TAF7L	ENST00000324762.10	TSL:2	c.523G>T	p.Val175Leu	missense	Exon 7 of 11	ENSP00000320283.6	Q5H9L4-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183097 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1096899 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362275

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26377

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 54097

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40465

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841005

Other (OTH) AF: 0.00 AC: 0 AN: 46056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.70		Loss of methylation at K266 (P = 0.0803)
MVP		0.70
MPC		0.92
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.68
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs768889307; hg19: chrX-100533091;