17-20204584-G-A

Variant names:

• chr17-20204584-G-A
• rs780084248
• NM_001243439.2:c.535G>A

Variant summary

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

The NM_001243439.2(SPECC1):​c.535G>A​(p.Ala179Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPECC1 NM_001243439.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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]

ENSG00000263494 (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=0.026842803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPECC1	NM_001243439.2	c.535G>A	p.Ala179Thr	missense_variant	Exon 4 of 15	ENST00000395527.9	NP_001230368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPECC1	ENST00000395527.9	c.535G>A	p.Ala179Thr	missense_variant	Exon 4 of 15	2	NM_001243439.2	ENSP00000378898.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251080 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461880 Hom.: 0 Cov.: 70 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535G>A (p.A179T) alteration is located in exon 1 (coding exon 1) of the SPECC1 gene. This alteration results from a G to A substitution at nucleotide position 535, causing the alanine (A) at amino acid position 179 to be replaced by a threonine (T). 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	0.070
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.016	T;.;T;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	.;T;D;D;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.027	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;N;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.91	.;N;N;.;N;N
REVEL	Benign	0.041
Sift	Benign	1.0	.;T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B
Vest4		0.033
MutPred		0.22		Gain of phosphorylation at A179 (P = 0.0126);Gain of phosphorylation at A179 (P = 0.0126);Gain of phosphorylation at A179 (P = 0.0126);.;.;.;
MVP		0.29
MPC		0.076
ClinPred		0.025	T
GERP RS		2.7
Varity_R		0.025
gMVP		0.065

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: rs780084248; hg19: chr17-20107897; COSMIC: COSV54959884; COSMIC: COSV54959884;