2-28849861-C-T

Position:

• chr2-28849861-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000334056.10(SPDYA):​c.862C>T​(p.His288Tyr) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPDYA ENST00000334056.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

Genes affected

SPDYA (HGNC:30613): (speedy/RINGO cell cycle regulator family member A) Enables protein kinase activator activity and protein kinase binding activity. Involved in several processes, including G1/S transition of mitotic cell cycle; positive regulation of cell population proliferation; and positive regulation of protein kinase activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TRMT61B (HGNC:26070): (tRNA methyltransferase 61B) Enables mRNA (adenine-N1-)-methyltransferase activity; rRNA (adenine) methyltransferase activity; and tRNA (adenine-N1-)-methyltransferase activity. Involved in mRNA methylation; mitochondrial tRNA methylation; and protein homooligomerization. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SPDYA (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06367099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPDYA	NM_182756.4	c.862C>T	p.His288Tyr	missense_variant	8/8	ENST00000334056.10	NP_877433.2
TRMT61B	NM_017910.4	c.*338G>A		3_prime_UTR_variant	7/7	ENST00000306108.10	NP_060380.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPDYA	ENST00000334056.10	c.862C>T	p.His288Tyr	missense_variant	8/8	1	NM_182756.4	ENSP00000335628.5
TRMT61B	ENST00000306108	c.*338G>A		3_prime_UTR_variant	7/7	1	NM_017910.4	ENSP00000302801.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 16, 2021

The c.862C>T (p.H288Y) alteration is located in exon 8 (coding exon 6) of the SPDYA gene. This alteration results from a C to T substitution at nucleotide position 862, causing the histidine (H) at amino acid position 288 to be replaced by a tyrosine (Y). 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	0.067
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	0.064
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.50	.;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	0.63	N;N;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.066
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.17	B;B
Vest4		0.23
MutPred		0.21		Gain of phosphorylation at H288 (P = 0.0328);Gain of phosphorylation at H288 (P = 0.0328);
MVP		0.28
MPC		0.82
ClinPred		0.43	T
GERP RS		4.6
Varity_R		0.069
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1668995001; hg19: chr2-29072727;