Genetic Variant SPEM2:p.Arg489Lys (chr17-7427457-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_175734.5(SPEM2):c.1466G>A(p.Arg489Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,601,096 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 4 hom. )

Consequence

SPEM2
NM_175734.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.81

Variant links:

Genes affected

SPEM2 (HGNC:27315): (SPEM family member 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SPEM2 links:

ENSG00000262880 (HGNC:):

ENSG00000262880 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008249491).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEM2	NM_175734.5 link	c.1466G>A	p.Arg489Lys	missense_variant	Exon 3 of 3	ENST00000333870.8	NP_783861.3	Q0P670
SPEM2	XM_006721471.4 link	c.1175G>A	p.Arg392Lys	missense_variant	Exon 3 of 3		XP_006721534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPEM2	ENST00000333870.8 link	c.1466G>A	p.Arg489Lys	missense_variant	Exon 3 of 3	1	NM_175734.5	ENSP00000328061.3	Q0P670
SPEM2	ENST00000574034.1 link	c.*750G>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000458799.1	I3L1F6
ENSG00000262880	ENST00000575310.1 link	n.272+5856G>A		intron_variant	Intron 3 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000402

AC:

AN:

233666

Hom.:

AF XY:

0.000409

AC XY:

AN XY:

127274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00906

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000961

Gnomad OTH exome

AF:

0.000878

GnomAD4 exome

AF:

0.000215

AC:

312

AN:

1448870

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

163

AN XY:

719204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00949

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000317

Gnomad4 OTH exome

AF:

0.000568

GnomAD4 genome

AF:

0.000230

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.000295

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000597

AC:

ExAC

AF:

0.000364

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1466G>A (p.R489K) alteration is located in exon 3 (coding exon 3) of the C17orf74 gene. This alteration results from a G to A substitution at nucleotide position 1466, causing the arginine (R) at amino acid position 489 to be replaced by a lysine (K). 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

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.016

Eigen

Benign

0.12

Eigen_PC

Benign

0.053

FATHMM_MKL

Benign

0.54

M_CAP

Benign

0.014

MetaRNN

Benign

0.0082

MetaSVM

Benign

-1.0

PROVEAN

Benign

-2.0

REVEL

Benign

0.12

Sift

Benign

0.053

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.23

MVP

0.13

MPC

0.44

ClinPred

0.073

GERP RS

4.3

Varity_R

0.19

gMVP

0.066

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over