NM_015346.4:c.4066T>G

Variant names:

• chr14-67783086-A-C
• rs149276487
• NM_015346.4:c.4066T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015346.4(ZFYVE26):​c.4066T>G​(p.Cys1356Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000668 in 1,613,060 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (24 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.96
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038672984).
• BP6: Variant 14-67783086-A-C is Benign according to our data. Variant chr14-67783086-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00123 (187/152134) while in subpopulation EAS AF = 0.0239 (123/5150). AF 95% confidence interval is 0.0205. There are 6 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.4066T>G	p.Cys1356Gly	missense	Exon 21 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.4066T>G	p.Cys1356Gly	missense	Exon 21 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.4066T>G	p.Cys1356Gly	missense	Exon 21 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.4203T>G		non_coding_transcript_exon	Exon 21 of 41

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152014 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0240

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00200 AC: 500 AN: 250552 AF XY: 0.00185

Gnomad AFR exome AF: 0.000866

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0246

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000610 AC: 891 AN: 1460926 Hom.: 24 Cov.: 34 AF XY: 0.000553 AC XY: 402 AN XY: 726612

African (AFR) AF: 0.000389 AC: 13 AN: 33436

American (AMR) AF: 0.000201 AC: 9 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.0119 AC: 473 AN: 39682

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111292

Other (OTH) AF: 0.00573 AC: 346 AN: 60350

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152134 Hom.: 6 Cov.: 33 AF XY: 0.000995 AC XY: 74 AN XY: 74386

African (AFR) AF: 0.000891 AC: 37 AN: 41522

American (AMR) AF: 0.000917 AC: 14 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0239 AC: 123 AN: 5150

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.000974 Hom.: 7

Bravo AF: 0.00149

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.087	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Benign	0.15	T
Sift4G	Benign	0.18	T
Polyphen		0.012	B
Vest4		0.75
MVP		0.35
MPC		0.75
ClinPred		0.046	T
GERP RS		4.4
gMVP		0.49
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs149276487; hg19: chr14-68249803;