rs12945577

Variant names:

• chr17-7432755-G-A
• rs12945577
• NM_001364708.1:c.3584G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001364708.1(SPEM3):​c.3584G>A​(p.Arg1195Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 398,562 control chromosomes in the GnomAD database, including 2,238 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1002 hom., cov: 32)
  • Exomes 𝑓: 0.090 (1236 hom.)
• Consequence: SPEM3 NM_001364708.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 10 publications found

Genes affected

SPEM3 (HGNC:53651): (SPEM family member 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286007 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018768013).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364708.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEM3	NM_001364708.1	MANE Select	c.3584G>A	p.Arg1195Lys	missense	Exon 3 of 3	NP_001351637.1
	SPEM3	NM_001364672.1		c.3485G>A	p.Arg1162Lys	missense	Exon 3 of 3	NP_001351601.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEM3	ENST00000636696.4	TSL:5 MANE Select	c.3584G>A	p.Arg1195Lys	missense	Exon 3 of 3	ENSP00000490274.1
	ENSG00000286007	ENST00000651314.1		n.197-3098G>A		intron	N/A	ENSP00000498964.1
	ENSG00000262880	ENST00000575310.1	TSL:2	n.273-8716G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16356 AN: 152106 Hom.: 996 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.0764

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.0905

GnomAD4 exome AF: 0.0902 AC: 22221 AN: 246338 Hom.: 1236 Cov.: 0 AF XY: 0.0882 AC XY: 11009 AN XY: 124832

African (AFR) AF: 0.130 AC: 931 AN: 7182

American (AMR) AF: 0.141 AC: 1051 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 433 AN: 9242

East Asian (EAS) AF: 0.150 AC: 3428 AN: 22894

South Asian (SAS) AF: 0.0796 AC: 239 AN: 3004

European-Finnish (FIN) AF: 0.178 AC: 3704 AN: 20840

Middle Eastern (MID) AF: 0.0316 AC: 41 AN: 1296

European-Non Finnish (NFE) AF: 0.0692 AC: 10939 AN: 158072

Other (OTH) AF: 0.0889 AC: 1455 AN: 16374

GnomAD4 genome AF: 0.108 AC: 16380 AN: 152224 Hom.: 1002 Cov.: 32 AF XY: 0.114 AC XY: 8485 AN XY: 74426

African (AFR) AF: 0.133 AC: 5522 AN: 41520

American (AMR) AF: 0.134 AC: 2047 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 168 AN: 3472

East Asian (EAS) AF: 0.156 AC: 808 AN: 5188

South Asian (SAS) AF: 0.0763 AC: 368 AN: 4826

European-Finnish (FIN) AF: 0.192 AC: 2027 AN: 10582

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0751 AC: 5109 AN: 68032

Other (OTH) AF: 0.0953 AC: 201 AN: 2110

Alfa AF: 0.0920 Hom.: 458

Bravo AF: 0.105

TwinsUK AF: 0.0709 AC: 263

ALSPAC AF: 0.0721 AC: 278

Asia WGS AF: 0.139 AC: 482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.0067	T
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	0.0019	T
PhyloP100		1.1
GERP RS		0.14
Varity_R		0.052
gMVP		0.0023

Splicing

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

Other links and lift over

dbSNP: rs12945577; hg19: chr17-7336074;