chr7-44001092-T-C

Variant names:

• chr7-44001092-T-C
• rs572510223
• NM_001378423.2:c.187T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378423.2(SPDYE1):​c.187T>C​(p.Cys63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,597,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SPDYE1 NM_001378423.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.232
• Publications: 0 publications found

Genes affected

SPDYE1 (HGNC:16408): (speedy/RINGO cell cycle regulator family member E1) This gene is located at chromosome 7p13 which is close to the Williams Beuren syndrome chromosome region 7q11.23. [provided by RefSeq, Jul 2008]

POLR2J4 (HGNC:):

POLR2J4 (HGNC:28195): (RNA polymerase II subunit J4 (pseudogene))

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042174786).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378423.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE1	NM_001378423.2	MANE Select	c.187T>C	p.Cys63Arg	missense	Exon 3 of 9	NP_001365352.1	A0A494C1S0
	SPDYE1	NM_175064.4		c.67T>C	p.Cys23Arg	missense	Exon 1 of 7	NP_778234.2
	POLR2J4	NR_003655.3		n.489+12501A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE1	ENST00000693451.1	MANE Select	c.187T>C	p.Cys63Arg	missense	Exon 3 of 9	ENSP00000509569.1	A0A494C1S0
	SPDYE1	ENST00000258704.3	TSL:1	c.67T>C	p.Cys23Arg	missense	Exon 1 of 7	ENSP00000258704.3	Q8NFV5
	POLR2J4	ENST00000427076.5	TSL:1	n.444+12501A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151328 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000760 AC: 1 AN: 131622 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000920

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446132 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 719794

African (AFR) AF: 0.0000598 AC: 2 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111912

Other (OTH) AF: 0.0000332 AC: 2 AN: 60180

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151446 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 74004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000243 AC: 1 AN: 41230

American (AMR) AF: 0.000132 AC: 2 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67824

Other (OTH) AF: 0.00 AC: 0 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.7
DANN	Benign	0.64
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.078	T
M_CAP	Benign	0.00045	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.48	N
PhyloP100		-0.23
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.042
Sift	Benign	0.10	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.39		Gain of MoRF binding (P = 0.0103)
MVP		0.061
MPC		2.1
ClinPred		0.038	T
PromoterAI		0.047	Neutral
Varity_R		0.23
gMVP		0.025
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs572510223; hg19: chr7-44040691;