11-134248443-T-A

Variant names:

• chr11-134248443-T-A
• NM_014174.3:c.673A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014174.3(THYN1):​c.673A>T​(p.Ser225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THYN1 NM_014174.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.929
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23204535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THYN1	NM_014174.3	c.673A>T	p.Ser225Cys	missense_variant	Exon 7 of 7	ENST00000341541.8	NP_054893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THYN1	ENST00000341541.8	c.673A>T	p.Ser225Cys	missense_variant	Exon 7 of 7	1	NM_014174.3	ENSP00000341657.3
THYN1	ENST00000392594.7	c.673A>T	p.Ser225Cys	missense_variant	Exon 8 of 8	1		ENSP00000376373.3
THYN1	ENST00000392595.6	c.673A>T	p.Ser225Cys	missense_variant	Exon 8 of 8	1		ENSP00000376374.2
THYN1	ENST00000352327.5	c.*21A>T		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000341452.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673A>T (p.S225C) alteration is located in exon 7 (coding exon 7) of the THYN1 gene. This alteration results from a A to T substitution at nucleotide position 673, causing the serine (S) at amino acid position 225 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	Benign	0.090
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T;T;T
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	.;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L;L;L
PhyloP100		0.93
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.099
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.95	P;P;P
Vest4		0.31
MutPred		0.27		Loss of phosphorylation at S225 (P = 0.0043);Loss of phosphorylation at S225 (P = 0.0043);Loss of phosphorylation at S225 (P = 0.0043);
MVP		0.11
MPC		0.61
ClinPred		0.59	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.14
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr11-134118337;