7-75496728-T-G

Variant names:

• chr7-75496728-T-G
• rs3973263
• NM_001306141.4:c.434T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001306141.4(SPDYE5):​c.434T>G​(p.Met145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 151,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPDYE5 NM_001306141.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.151
• Publications: 0 publications found

Genes affected

SPDYE5 (HGNC:35464): (speedy/RINGO cell cycle regulator family member E5) Predicted to enable protein kinase binding activity. Predicted to be involved in positive regulation of cyclin-dependent protein serine/threonine kinase activity. [provided by Alliance of Genome Resources, Apr 2022]

PMS2P3 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031719863).
• BP6: Variant 7-75496728-T-G is Benign according to our data. Variant chr7-75496728-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3168782.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306141.4. 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
	SPDYE5	NM_001306141.4	MANE Select	c.434T>G	p.Met145Arg	missense	Exon 4 of 9	NP_001293070.1	A6NIY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE5	ENST00000625065.4	TSL:5 MANE Select	c.434T>G	p.Met145Arg	missense	Exon 4 of 9	ENSP00000485398.1	A6NIY4
	PMS2P3	ENST00000845725.1		n.435-5105A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 151064 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000178 AC: 27 AN: 151984 AF XY: 0.000172

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.000719

Gnomad EAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000569 AC: 82 AN: 1442060 Hom.: 0 Cov.: 33 AF XY: 0.0000627 AC XY: 45 AN XY: 717456

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

African (AFR) AF: 0.0000300 AC: 1 AN: 33366

American (AMR) AF: 0.0000681 AC: 3 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.000346 AC: 9 AN: 26002

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39642

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85568

European-Finnish (FIN) AF: 0.0000257 AC: 1 AN: 38970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1110300

Other (OTH) AF: 0.0000999 AC: 6 AN: 60032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151180 Hom.: 0 Cov.: 23 AF XY: 0.000136 AC XY: 10 AN XY: 73794

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

African (AFR) AF: 0.0000970 AC: 4 AN: 41220

American (AMR) AF: 0.0000660 AC: 1 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3454

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67736

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000373263), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000260 Hom.: 0

ExAC AF: 0.000124 AC: 14

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.049
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.42
DANN	Benign	0.20
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.032	T
PhyloP100		-0.15
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	1.0	T
Vest4		0.14
MVP		0.072
GERP RS		-0.91
Varity_R		0.37
gMVP		0.018

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

Other links and lift over

dbSNP: rs3973263; hg19: chr7-75126051;