14-67785952-G-C

Variant names:

• chr14-67785952-G-C
• rs7156492
• NM_015346.4:c.3210C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.3210C>G​(p.Pro1070Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,614,134 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1070P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (315 hom., cov: 32)
  • Exomes 𝑓: 0.019 (529 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0830
• Publications: 7 publications found

Genes affected

ZFYVE26 (HGNC:20761): (zinc finger FYVE-type containing 26) This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

ZFYVE26 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 14-67785952-G-C is Benign according to our data. Variant chr14-67785952-G-C is described in ClinVar as Benign. ClinVar VariationId is 130779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.083 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.3210C>G	p.Pro1070Pro	synonymous	Exon 18 of 42	NP_056161.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.3210C>G	p.Pro1070Pro	synonymous	Exon 18 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.3210C>G	p.Pro1070Pro	synonymous	Exon 18 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.3347C>G		non_coding_transcript_exon	Exon 18 of 41

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6914 AN: 152126 Hom.: 315 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00895

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0420

GnomAD2 exomes AF: 0.0246 AC: 6182 AN: 251408 AF XY: 0.0228

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0518

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0195 AC: 28494 AN: 1461890 Hom.: 529 Cov.: 35 AF XY: 0.0192 AC XY: 13996 AN XY: 727246

African (AFR) AF: 0.119 AC: 3999 AN: 33480

American (AMR) AF: 0.0114 AC: 509 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 299 AN: 26136

East Asian (EAS) AF: 0.0602 AC: 2389 AN: 39700

South Asian (SAS) AF: 0.0194 AC: 1670 AN: 86258

European-Finnish (FIN) AF: 0.00929 AC: 496 AN: 53416

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17482 AN: 1112012

Other (OTH) AF: 0.0238 AC: 1438 AN: 60396

GnomAD4 genome AF: 0.0455 AC: 6927 AN: 152244 Hom.: 315 Cov.: 32 AF XY: 0.0441 AC XY: 3280 AN XY: 74432

African (AFR) AF: 0.121 AC: 5005 AN: 41526

American (AMR) AF: 0.0196 AC: 299 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.0522 AC: 270 AN: 5176

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4826

European-Finnish (FIN) AF: 0.00895 AC: 95 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1023 AN: 68016

Other (OTH) AF: 0.0416 AC: 88 AN: 2116

Alfa AF: 0.00821 Hom.: 3

Bravo AF: 0.0507

EpiCase AF: 0.0159

EpiControl AF: 0.0180

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 15 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.1
DANN	Benign	0.71
PhyloP100		0.083
Mutation Taster		=97/3	polymorphism (auto)

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: rs7156492; hg19: chr14-68252669; COSMIC: COSV61325750;