rs12945577

Positions:

• chr17-7432755-G-A

Variant summary

Our verdict is Benign. Variant got -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

Genes affected

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

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEM3	NM_001364708.1	c.3584G>A	p.Arg1195Lys	missense_variant	3/3	ENST00000636696.4	NP_001351637.1
SPEM3	NM_001364672.1	c.3485G>A	p.Arg1162Lys	missense_variant	3/3		NP_001351601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEM3	ENST00000636696.4	c.3584G>A	p.Arg1195Lys	missense_variant	3/3	5	NM_001364708.1	ENSP00000490274	P1

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

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.0469

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.0692

Gnomad4 OTH exome AF: 0.0889

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

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0484

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.0763

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.0751

Gnomad4 OTH AF: 0.0953

Alfa AF: 0.0941 Hom.: 292

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 v4.3

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs12945577; hg19: chr17-7336074;