17-20204815-T-G

Position:

• chr17-20204815-T-G

Variant summary

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

The NM_001243439.2(SPECC1):​c.766T>G​(p.Tyr256Asp) 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. 13/21 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: SPECC1 NM_001243439.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

Genes affected

SPECC1 (HGNC:30615): (sperm antigen with calponin homology and coiled-coil domains 1) The protein encoded by this gene belongs to the cytospin-A family. It is localized in the nucleus, and highly expressed in testis and some cancer cell lines. A chromosomal translocation involving this gene and platelet-derived growth factor receptor, beta gene (PDGFRB) may be a cause of juvenile myelomonocytic leukemia. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

(HGNC:):

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=0.22147122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPECC1	NM_001243439.2	c.766T>G	p.Tyr256Asp	missense_variant	4/15	ENST00000395527.9	NP_001230368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPECC1	ENST00000395527.9	c.766T>G	p.Tyr256Asp	missense_variant	4/15	2	NM_001243439.2	ENSP00000378898	A2
	ENST00000580225.1	n.105+19629T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Nov 13, 2023

The c.766T>G (p.Y256D) alteration is located in exon 1 (coding exon 1) of the SPECC1 gene. This alteration results from a T to G substitution at nucleotide position 766, causing the tyrosine (Y) at amino acid position 256 to be replaced by an aspartic acid (D). 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	0.083
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T;.;T;.;.;.
Eigen	Benign	-0.011
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.85	.;T;D;D;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.96	.;N;N;.;N;N
REVEL	Benign	0.061
Sift	Benign	0.084	.;T;T;.;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T
Polyphen		0.73	P;P;P;D;.;P
Vest4		0.54
MutPred		0.17		Loss of phosphorylation at Y256 (P = 0.0173);Loss of phosphorylation at Y256 (P = 0.0173);Loss of phosphorylation at Y256 (P = 0.0173);.;.;.;
MVP		0.67
MPC		0.23
ClinPred		0.61	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.080
gMVP		0.16

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: rs1597968241; hg19: chr17-20108128;