NM_001385875.1:c.244G>A

Variant names:

• chr10-97743140-G-A
• rs17108378
• NM_001385875.1:c.244G>A

Variant summary

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

The NM_001385875.1(ZFYVE27):​c.244G>A​(p.Val82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,614,168 control chromosomes in the GnomAD database, including 900 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (73 hom., cov: 32)
  • Exomes 𝑓: 0.031 (827 hom.)
• Consequence: ZFYVE27 NM_001385875.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.14
• Publications: 19 publications found

Genes affected

ZFYVE27 (HGNC:26559): (zinc finger FYVE-type containing 27) This gene encodes a protein with several transmembrane domains, a Rab11-binding domain and a lipid-binding FYVE finger domain. The encoded protein appears to promote neurite formation. A mutation in this gene has been reported to be associated with hereditary spastic paraplegia, however the pathogenicity of the mutation, which may simply represent a polymorphism, is unclear. [provided by RefSeq, Mar 2010]

ZFYVE27 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 33

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020341873).
• BP6: Variant 10-97743140-G-A is Benign according to our data. Variant chr10-97743140-G-A is described in ClinVar as Benign. ClinVar VariationId is 130785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385875.1. 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
	ZFYVE27	NM_001385875.1	MANE Select	c.244G>A	p.Val82Ile	missense	Exon 3 of 13	NP_001372804.1	Q5T4F4-1
	ZFYVE27	NM_001385876.1		c.244G>A	p.Val82Ile	missense	Exon 3 of 13	NP_001372805.1
	ZFYVE27	NM_001002261.4		c.244G>A	p.Val82Ile	missense	Exon 3 of 13	NP_001002261.1	Q5T4F4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE27	ENST00000684270.1	MANE Select	c.244G>A	p.Val82Ile	missense	Exon 3 of 13	ENSP00000506975.1	Q5T4F4-1
	ZFYVE27	ENST00000393677.8	TSL:1	c.244G>A	p.Val82Ile	missense	Exon 3 of 13	ENSP00000377282.3	Q5T4F4-1
	ZFYVE27	ENST00000423811.3	TSL:5	c.244G>A	p.Val82Ile	missense	Exon 3 of 13	ENSP00000409594.2	Q5T4F4-3

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4483 AN: 152192 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0302

GnomAD2 exomes AF: 0.0321 AC: 8063 AN: 251492 AF XY: 0.0340

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0434

Gnomad EAS exome AF: 0.0379

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0308 AC: 45083 AN: 1461858 Hom.: 827 Cov.: 32 AF XY: 0.0318 AC XY: 23162 AN XY: 727230

African (AFR) AF: 0.0295 AC: 987 AN: 33478

American (AMR) AF: 0.0177 AC: 790 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 1124 AN: 26134

East Asian (EAS) AF: 0.0391 AC: 1551 AN: 39700

South Asian (SAS) AF: 0.0558 AC: 4810 AN: 86254

European-Finnish (FIN) AF: 0.0195 AC: 1044 AN: 53420

Middle Eastern (MID) AF: 0.0324 AC: 187 AN: 5768

European-Non Finnish (NFE) AF: 0.0294 AC: 32650 AN: 1111984

Other (OTH) AF: 0.0321 AC: 1940 AN: 60396

GnomAD4 genome AF: 0.0295 AC: 4486 AN: 152310 Hom.: 73 Cov.: 32 AF XY: 0.0294 AC XY: 2189 AN XY: 74486

African (AFR) AF: 0.0295 AC: 1224 AN: 41562

American (AMR) AF: 0.0286 AC: 438 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3470

East Asian (EAS) AF: 0.0358 AC: 186 AN: 5192

South Asian (SAS) AF: 0.0527 AC: 254 AN: 4822

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0292 AC: 1984 AN: 68028

Other (OTH) AF: 0.0299 AC: 63 AN: 2110

Alfa AF: 0.0306 Hom.: 330

Bravo AF: 0.0301

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0285 AC: 110

ESP6500AA AF: 0.0327 AC: 144

ESP6500EA AF: 0.0315 AC: 271

ExAC AF: 0.0334 AC: 4055

Asia WGS AF: 0.0370 AC: 128 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0308

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 33 (2)
-	-	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	0.056
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.046
DANN	Benign	0.78
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.018
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.064
ClinPred		0.0029	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.018
gMVP		0.085
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17108378; hg19: chr10-99502897;