rs112976233

Variant names:

• chr14-88437877-T-C
• rs112976233
• NM_018418.5:c.1255T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_018418.5(SPATA7):​c.1255T>C​(p.Leu419Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,608,652 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L419L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (44 hom.)
• Consequence: SPATA7 NM_018418.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.03
• Publications: 2 publications found

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]

SPATA7 Gene-Disease associations (from GenCC):

• Leber congenital amaurosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 14-88437877-T-C is Benign according to our data. Variant chr14-88437877-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534952.
• BP7: Synonymous conserved (PhyloP=2.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2170/152268) while in subpopulation AFR AF = 0.0488 (2027/41542). AF 95% confidence interval is 0.047. There are 51 homozygotes in GnomAd4. There are 1032 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018418.5. 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
	SPATA7	NM_018418.5	MANE Select	c.1255T>C	p.Leu419Leu	synonymous	Exon 12 of 12	NP_060888.2
	SPATA7	NM_001040428.4		c.1159T>C	p.Leu387Leu	synonymous	Exon 11 of 11	NP_001035518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPATA7	ENST00000393545.9	TSL:1 MANE Select	c.1255T>C	p.Leu419Leu	synonymous	Exon 12 of 12	ENSP00000377176.4
	SPATA7	ENST00000356583.9	TSL:1	c.1159T>C	p.Leu387Leu	synonymous	Exon 11 of 11	ENSP00000348991.5
	SPATA7	ENST00000556553.5	TSL:1	c.1159T>C	p.Leu387Leu	synonymous	Exon 12 of 12	ENSP00000451128.1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2157 AN: 152150 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00728

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00367 AC: 908 AN: 247576 AF XY: 0.00281

Gnomad AFR exome AF: 0.0492

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00148 AC: 2149 AN: 1456384 Hom.: 44 Cov.: 32 AF XY: 0.00133 AC XY: 966 AN XY: 723854

African (AFR) AF: 0.0503 AC: 1669 AN: 33148

American (AMR) AF: 0.00323 AC: 142 AN: 43992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.000212 AC: 18 AN: 84870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00332 AC: 19 AN: 5720

European-Non Finnish (NFE) AF: 0.0000928 AC: 103 AN: 1109674

Other (OTH) AF: 0.00329 AC: 198 AN: 60142

GnomAD4 genome AF: 0.0143 AC: 2170 AN: 152268 Hom.: 51 Cov.: 32 AF XY: 0.0139 AC XY: 1032 AN XY: 74444

African (AFR) AF: 0.0488 AC: 2027 AN: 41542

American (AMR) AF: 0.00727 AC: 111 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00730 Hom.: 14

Bravo AF: 0.0165

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Leber congenital amaurosis 3 (2)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.6
DANN	Benign	0.72
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

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: rs112976233; hg19: chr14-88904221;