rs34852231

Variant names:

• chr14-67767710-A-G
• rs34852231
• NM_015346.4:c.5784T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015346.4(ZFYVE26):​c.5784T>C​(p.Tyr1928Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,614,158 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (42 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (52 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.21
• Publications: 4 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), Orphanet, Myriad Women’s Health, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-67767710-A-G is Benign according to our data. Variant chr14-67767710-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0152 (2316/152276) while in subpopulation AFR AF = 0.0436 (1811/41542). AF 95% confidence interval is 0.0419. There are 42 homozygotes in GnomAd4. There are 1061 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

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.5784T>C	p.Tyr1928Tyr	synonymous	Exon 31 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.5784T>C	p.Tyr1928Tyr	synonymous	Exon 31 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.5784T>C	p.Tyr1928Tyr	synonymous	Exon 31 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.5921T>C		non_coding_transcript_exon	Exon 31 of 41

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2313 AN: 152158 Hom.: 42 Cov.: 31

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00686 AC: 1724 AN: 251390 AF XY: 0.00622

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00484 AC: 7077 AN: 1461882 Hom.: 52 Cov.: 30 AF XY: 0.00487 AC XY: 3545 AN XY: 727242

African (AFR) AF: 0.0427 AC: 1431 AN: 33480

American (AMR) AF: 0.00601 AC: 269 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 306 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00437 AC: 377 AN: 86258

European-Finnish (FIN) AF: 0.00146 AC: 78 AN: 53418

Middle Eastern (MID) AF: 0.0258 AC: 149 AN: 5768

European-Non Finnish (NFE) AF: 0.00359 AC: 3989 AN: 1112006

Other (OTH) AF: 0.00790 AC: 477 AN: 60396

GnomAD4 genome AF: 0.0152 AC: 2316 AN: 152276 Hom.: 42 Cov.: 31 AF XY: 0.0143 AC XY: 1061 AN XY: 74444

African (AFR) AF: 0.0436 AC: 1811 AN: 41542

American (AMR) AF: 0.00772 AC: 118 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00397 AC: 270 AN: 68032

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.00868 Hom.: 60

Bravo AF: 0.0173

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00646

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.5
DANN	Benign	0.53
PhyloP100		2.2
Mutation Taster		=99/1	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: rs34852231; hg19: chr14-68234427;