5-893075-A-T

Variant names:

• chr5-893075-A-T
• rs780778324
• NM_004237.4:c.77A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_004237.4(TRIP13):​c.77A>T​(p.His26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,444,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. H26R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TRIP13 NM_004237.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.936

Genes affected

TRIP13 (HGNC:12307): (thyroid hormone receptor interactor 13) This gene encodes a protein that interacts with thyroid hormone receptors, also known as hormone-dependent transcription factors. The gene product interacts specifically with the ligand binding domain. This gene is one of several that may play a role in early-stage non-small cell lung cancer. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-893075-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.124539495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIP13	NM_004237.4	c.77A>T	p.His26Leu	missense_variant	Exon 1 of 13	ENST00000166345.8	NP_004228.1
TRIP13	NM_001166260.2	c.77A>T	p.His26Leu	missense_variant	Exon 1 of 9		NP_001159732.1
TRIP13	XM_011514163.2	c.77A>T	p.His26Leu	missense_variant	Exon 1 of 14		XP_011512465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIP13	ENST00000166345.8	c.77A>T	p.His26Leu	missense_variant	Exon 1 of 13	1	NM_004237.4	ENSP00000166345.3
TRIP13	ENST00000512024.5	n.192A>T		non_coding_transcript_exon_variant	Exon 1 of 9	1
TRIP13	ENST00000508456.1	n.51A>T		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000460 AC: 1 AN: 217592 Hom.: 0 AF XY: 0.00000836 AC XY: 1 AN XY: 119632

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1444434 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000837 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.72
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.46	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.20
Sift	Benign	0.68	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.37		Loss of disorder (P = 0.0308);
MVP		0.16
MPC		0.73
ClinPred		0.021	T
GERP RS		-4.6
Varity_R		0.14
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs780778324; hg19: chr5-893190;