14-67767822-T-C

Variant names:

• chr14-67767822-T-C
• rs3742883
• NM_015346.4:c.5672A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015346.4(ZFYVE26):​c.5672A>G​(p.Asn1891Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,614,112 control chromosomes in the GnomAD database, including 764,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67316 hom., cov: 32)
  • Exomes 𝑓: 0.98 (697040 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.377
• Publications: 29 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=7.4522825E-7).
• BP6: Variant 14-67767822-T-C is Benign according to our data. Variant chr14-67767822-T-C is described in ClinVar as Benign. ClinVar VariationId is 130783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.98 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.5672A>G	p.Asn1891Ser	missense	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.5672A>G	p.Asn1891Ser	missense	Exon 31 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.5672A>G	p.Asn1891Ser	missense	Exon 31 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.5809A>G		non_coding_transcript_exon	Exon 31 of 41

Frequencies

GnomAD3 genomes AF: 0.939 AC: 142761 AN: 152108 Hom.: 67275 Cov.: 32

Gnomad AFR AF: 0.851

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.922

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.971

Gnomad FIN AF: 0.993

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.987

Gnomad OTH AF: 0.951

GnomAD2 exomes AF: 0.954 AC: 239844 AN: 251352 AF XY: 0.961

Gnomad AFR exome AF: 0.846

Gnomad AMR exome AF: 0.894

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 0.857

Gnomad FIN exome AF: 0.993

Gnomad NFE exome AF: 0.986

Gnomad OTH exome AF: 0.972

GnomAD4 exome AF: 0.976 AC: 1426640 AN: 1461886 Hom.: 697040 Cov.: 68 AF XY: 0.977 AC XY: 710282 AN XY: 727244

African (AFR) AF: 0.849 AC: 28422 AN: 33480

American (AMR) AF: 0.896 AC: 40086 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 25997 AN: 26136

East Asian (EAS) AF: 0.854 AC: 33918 AN: 39698

South Asian (SAS) AF: 0.973 AC: 83936 AN: 86258

European-Finnish (FIN) AF: 0.991 AC: 52961 AN: 53420

Middle Eastern (MID) AF: 0.984 AC: 5675 AN: 5768

European-Non Finnish (NFE) AF: 0.987 AC: 1097019 AN: 1112008

Other (OTH) AF: 0.971 AC: 58626 AN: 60396

GnomAD4 genome AF: 0.938 AC: 142863 AN: 152226 Hom.: 67316 Cov.: 32 AF XY: 0.938 AC XY: 69811 AN XY: 74422

African (AFR) AF: 0.851 AC: 35302 AN: 41480

American (AMR) AF: 0.922 AC: 14103 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3457 AN: 3472

East Asian (EAS) AF: 0.858 AC: 4431 AN: 5166

South Asian (SAS) AF: 0.971 AC: 4686 AN: 4826

European-Finnish (FIN) AF: 0.993 AC: 10542 AN: 10620

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.987 AC: 67140 AN: 68042

Other (OTH) AF: 0.950 AC: 2005 AN: 2110

Alfa AF: 0.969 Hom.: 320008

Bravo AF: 0.928

TwinsUK AF: 0.984 AC: 3647

ALSPAC AF: 0.988 AC: 3807

ESP6500AA AF: 0.856 AC: 3770

ESP6500EA AF: 0.986 AC: 8478

ExAC AF: 0.955 AC: 115895

Asia WGS AF: 0.916 AC: 3185 AN: 3478

EpiCase AF: 0.988

EpiControl AF: 0.987

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hereditary spastic paraplegia 15 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.083
DANN	Benign	0.11
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	7.5e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.38
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.015
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.13
ClinPred		0.00015	T
GERP RS		-2.7
gMVP		0.078
Mutation Taster		=100/0	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: rs3742883; hg19: chr14-68234539; COSMIC: COSV107418190;