rs781269466

Variant names:

• chr11-134248811-T-C
• rs781269466
• NM_014174.3:c.629A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014174.3(THYN1):​c.629A>G​(p.Gln210Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q210H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: THYN1 NM_014174.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002219
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.716
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06767726).
• BP6: Variant 11-134248811-T-C is Benign according to our data. Variant chr11-134248811-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2521283.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THYN1	NM_014174.3	c.629A>G	p.Gln210Arg	missense_variant, splice_region_variant	Exon 6 of 7	ENST00000341541.8	NP_054893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THYN1	ENST00000341541.8	c.629A>G	p.Gln210Arg	missense_variant, splice_region_variant	Exon 6 of 7	1	NM_014174.3	ENSP00000341657.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251364 AF XY: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 11, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.033	T;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	.;.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	L;L;L
PhyloP100		0.72
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.21
MutPred		0.39		Gain of phosphorylation at T209 (P = 0.1918);Gain of phosphorylation at T209 (P = 0.1918);Gain of phosphorylation at T209 (P = 0.1918);
MVP		0.13
MPC		0.19
ClinPred		0.039	T
GERP RS		-0.24
Varity_R		0.065
gMVP		0.13
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.030		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: rs781269466; hg19: chr11-134118705;