2-170716845-G-T

Variant names:

• chr2-170716845-G-T
• rs1700080515
• NM_001003845.3:c.638G>T

Variant summary

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

The NM_001003845.3(SP5):​c.638G>T​(p.Cys213Phe) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SP5 NM_001003845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

Genes affected

SP5 (HGNC:14529): (Sp5 transcription factor) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within bone morphogenesis; cellular response to organic cyclic compound; and post-anal tail morphogenesis. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ERICH2-DT (HGNC:55686): (ERICH2 divergent transcript)

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=0.20126781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP5	NM_001003845.3	c.638G>T	p.Cys213Phe	missense_variant	Exon 2 of 2	ENST00000375281.4	NP_001003845.1
SP5	XM_005246542.5	c.770G>T	p.Cys257Phe	missense_variant	Exon 2 of 2		XP_005246599.1
SP5	XM_047444264.1	c.410G>T	p.Cys137Phe	missense_variant	Exon 2 of 2		XP_047300220.1
ERICH2-DT	NR_110185.1	n.376+6659C>A		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP5	ENST00000375281.4	c.638G>T	p.Cys213Phe	missense_variant	Exon 2 of 2	1	NM_001003845.3	ENSP00000364430.3
ERICH2-DT	ENST00000662274.1	n.859+6659C>A		intron_variant	Intron 5 of 5
ERICH2-DT	ENST00000671292.1	n.336+6659C>A		intron_variant	Intron 4 of 4
ERICH2-DT	ENST00000690230.1	n.404+6659C>A		intron_variant	Intron 5 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1286222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 632244

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.638G>T (p.C213F) alteration is located in exon 2 (coding exon 2) of the SP5 gene. This alteration results from a G to T substitution at nucleotide position 638, causing the cysteine (C) at amino acid position 213 to be replaced by a phenylalanine (F). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Benign	0.85
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.16	B
Vest4		0.25
MutPred		0.26		Gain of helix (P = 0.132);
MVP		0.067
ClinPred		0.27	T
GERP RS		3.8
Varity_R		0.41
gMVP		0.53

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: rs1700080515; hg19: chr2-171573355;