1-222561466-G-C

Variant names:

• chr1-222561466-G-C
• rs1659912774
• NM_005681.4:c.1138C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005681.4(TAF1A):​c.1138C>G​(p.Pro380Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAF1A NM_005681.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

Genes affected

TAF1A (HGNC:11532): (TATA-box binding protein associated factor, RNA polymerase I subunit A) This gene encodes a subunit of the RNA polymerase I complex, Selectivity Factor I (SLI). The encoded protein is a TATA box-binding protein-associated factor that plays a role in the assembly of the RNA polymerase I preinitiation complex. Alternate splicing results in multiple transcript variants encoding multiple isoforms.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF1A	NM_005681.4	c.1138C>G	p.Pro380Ala	missense_variant	Exon 10 of 11	ENST00000352967.9	NP_005672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF1A	ENST00000352967.9	c.1138C>G	p.Pro380Ala	missense_variant	Exon 10 of 11	1	NM_005681.4	ENSP00000327072.6
TAF1A	ENST00000350027.8	c.1138C>G	p.Pro380Ala	missense_variant	Exon 10 of 12	2		ENSP00000339976.4
TAF1A	ENST00000366890.5	c.796C>G	p.Pro266Ala	missense_variant	Exon 9 of 11	2		ENSP00000355856.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1138C>G (p.P380A) alteration is located in exon 10 (coding exon 9) of the TAF1A gene. This alteration results from a C to G substitution at nucleotide position 1138, causing the proline (P) at amino acid position 380 to be replaced by an alanine (A). 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T;.
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	.;M;M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.4	D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.078	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.72
MutPred		0.51		.;Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);
MVP		0.89
MPC		0.89
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.17
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1659912774; hg19: chr1-222734808;