rs76327447

Variant names:

• chr14-67761549-C-T
• rs76327447
• NM_015346.4:c.6405G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.6405G>A​(p.Leu2135Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,160 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (146 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.319
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 14-67761549-C-T is Benign according to our data. Variant chr14-67761549-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.319 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0724 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.6405G>A	p.Leu2135Leu	synonymous	Exon 35 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.6405G>A	p.Leu2135Leu	synonymous	Exon 35 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.6405G>A	p.Leu2135Leu	synonymous	Exon 35 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.7160G>A		non_coding_transcript_exon	Exon 34 of 41

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152184 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0789

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00605 AC: 1520 AN: 251136 AF XY: 0.00550

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0758

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00266 AC: 3887 AN: 1461858 Hom.: 146 Cov.: 31 AF XY: 0.00260 AC XY: 1891 AN XY: 727230

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26134

East Asian (EAS) AF: 0.0801 AC: 3178 AN: 39700

South Asian (SAS) AF: 0.00129 AC: 111 AN: 86252

European-Finnish (FIN) AF: 0.000974 AC: 52 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1112002

Other (OTH) AF: 0.00450 AC: 272 AN: 60394

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152302 Hom.: 17 Cov.: 33 AF XY: 0.00355 AC XY: 264 AN XY: 74458

African (AFR) AF: 0.000313 AC: 13 AN: 41562

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.0787 AC: 408 AN: 5184

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68028

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.000767 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.0330 AC: 117 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

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	-0.38
CADD	Benign	6.0
DANN	Benign	0.72
PhyloP100		0.32
PromoterAI		-0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76327447; hg19: chr14-68228266; COSMIC: COSV61329633; COSMIC: COSV61329633;