11-134250285-C-A

Variant names:

• chr11-134250285-C-A
• rs766096798
• NM_014174.3:c.281G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014174.3(THYN1):​c.281G>T​(p.Arg94Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R94P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THYN1 NM_014174.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.23
• Publications: 2 publications found

Genes affected

THYN1 (HGNC:29560): (thymocyte nuclear protein 1) This gene encodes a protein that is highly conserved among vertebrates and plant species and may be involved in the induction of apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THYN1	NM_014174.3	c.281G>T	p.Arg94Leu	missense_variant	Exon 3 of 7	ENST00000341541.8	NP_054893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THYN1	ENST00000341541.8	c.281G>T	p.Arg94Leu	missense_variant	Exon 3 of 7	1	NM_014174.3	ENSP00000341657.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;D;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.9	H;H;H;H
PhyloP100		7.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.89		Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);
MVP		0.055
MPC		0.49
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.83
gMVP		0.71
Mutation Taster		=33/67	disease causing

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: rs766096798; hg19: chr11-134120179;