15-41561231-G-T

Position:

• chr15-41561231-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006293.4(TYRO3):​c.229G>T​(p.Val77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TYRO3 NM_006293.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

Genes affected

TYRO3 (HGNC:12446): (TYRO3 protein tyrosine kinase) The gene is part of a 3-member transmembrane receptor kinase receptor family with a processed pseudogene distal on chromosome 15. The encoded protein is activated by the products of the growth arrest-specific gene 6 and protein S genes and is involved in controlling cell survival and proliferation, spermatogenesis, immunoregulation and phagocytosis. The encoded protein has also been identified as a cell entry factor for Ebola and Marburg viruses. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07915971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYRO3	NM_006293.4	c.229G>T	p.Val77Leu	missense_variant	2/19	ENST00000263798.8	NP_006284.2
TYRO3	NM_001330264.2	c.94G>T	p.Val32Leu	missense_variant	2/19		NP_001317193.1
TYRO3	XM_017022543.3	c.229G>T	p.Val77Leu	missense_variant	2/19		XP_016878032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYRO3	ENST00000263798.8	c.229G>T	p.Val77Leu	missense_variant	2/19	1	NM_006293.4	ENSP00000263798.3
TYRO3	ENST00000559066.5	c.94G>T	p.Val32Leu	missense_variant	2/19	5		ENSP00000454050.1
TYRO3	ENST00000560992.1	n.260G>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.229G>T (p.V77L) alteration is located in exon 2 (coding exon 2) of the TYRO3 gene. This alteration results from a G to T substitution at nucleotide position 229, causing the valine (V) at amino acid position 77 to be replaced by a leucine (L). 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	0.082
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.86	D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-1.0	.;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.92	N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0030	.;B
Vest4		0.27
MutPred		0.50		.;Loss of ubiquitination at K78 (P = 0.1037);
MVP		0.12
MPC		0.39
ClinPred		0.046	T
GERP RS		-0.75
Varity_R		0.091
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-41853429;