14-88385822-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018418.5(SPATA7):c.4G>A(p.Asp2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,604,026 control chromosomes in the GnomAD database, including 126,073 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (9059 hom., cov: 33)
  • Exomes 𝑓: 0.39 (117014 hom.)
• Consequence: SPATA7 NM_018418.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.251

Genes affected

SPATA7 (HGNC:20423): (spermatogenesis associated 7) This gene, originally isolated from testis, is also expressed in retina. Mutations in this gene are associated with Leber congenital amaurosis and juvenile retinitis pigmentosa. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.6560168E-4).
• BP6: Variant 14-88385822-G-A is Benign according to our data. Variant chr14-88385822-G-A is described in ClinVar as [Benign]. Clinvar id is 95907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-88385822-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPATA7	NM_018418.5	c.4G>A	p.Asp2Asn	missense_variant	1/12	ENST00000393545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPATA7	ENST00000393545.9	c.4G>A	p.Asp2Asn	missense_variant	1/12	1	NM_018418.5	P2

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46699 AN: 152020 Hom.: 9063 Cov.: 33

Gnomad AFR AF: 0.0974

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.0427

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.355

GnomAD3 exomes AF: 0.329 AC: 76069 AN: 231254 Hom.: 14853 AF XY: 0.337 AC XY: 42249 AN XY: 125228

Gnomad AFR exome AF: 0.0878

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.0341

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.389 AC: 565174 AN: 1451888 Hom.: 117014 Cov.: 44 AF XY: 0.388 AC XY: 279820 AN XY: 721190

Gnomad4 AFR exome AF: 0.0816

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.402

Gnomad4 EAS exome AF: 0.0420

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.518

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.307 AC: 46675 AN: 152138 Hom.: 9059 Cov.: 33 AF XY: 0.311 AC XY: 23123 AN XY: 74366

Gnomad4 AFR AF: 0.0972

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.0424

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.350

Alfa AF: 0.386 Hom.: 9491

Bravo AF: 0.276

TwinsUK AF: 0.417 AC: 1547

ALSPAC AF: 0.426 AC: 1643

ESP6500AA AF: 0.106 AC: 466

ESP6500EA AF: 0.391 AC: 3358

ExAC AF: 0.317 AC: 38241

Asia WGS AF: 0.147 AC: 510 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Leber congenital amaurosis 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.51	D
MetaRNN	Benign	0.00047	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L;L;L;.;.;L
MutationTaster	Benign	0.87	P;P;P;P
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.62	N;N;N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.058	T;T;T;D;D;T
Sift4G	Benign	0.21	T;T;T;.;T;T
Polyphen		0.015	B;P;B;.;.;.
Vest4		0.038
MPC		0.14
ClinPred		0.039	T
GERP RS		2.2
Varity_R		0.059
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs4904448; hg19: chr14-88852166; COSMIC: COSV50416109;