10-97738539-C-T

Variant names:

• chr10-97738539-C-T
• rs140812293
• NM_001385875.1:c.62C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001385875.1(ZFYVE27):​c.62C>T​(p.Ala21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,614,172 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (27 hom.)
• Consequence: ZFYVE27 NM_001385875.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.98
• Publications: 5 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032285154).
• BP6: Variant 10-97738539-C-T is Benign according to our data. Variant chr10-97738539-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 582 AD gene.

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.62C>T	p.Ala21Val	missense	Exon 2 of 13	NP_001372804.1	Q5T4F4-1
	ZFYVE27	NM_001385876.1		c.62C>T	p.Ala21Val	missense	Exon 2 of 13	NP_001372805.1
	ZFYVE27	NM_001002261.4		c.62C>T	p.Ala21Val	missense	Exon 2 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.62C>T	p.Ala21Val	missense	Exon 2 of 13	ENSP00000506975.1	Q5T4F4-1
	ZFYVE27	ENST00000393677.8	TSL:1	c.62C>T	p.Ala21Val	missense	Exon 2 of 13	ENSP00000377282.3	Q5T4F4-1
	ZFYVE27	ENST00000423811.3	TSL:5	c.62C>T	p.Ala21Val	missense	Exon 2 of 13	ENSP00000409594.2	Q5T4F4-3

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152162 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00356 AC: 895 AN: 251484 AF XY: 0.00338

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00556 AC: 8129 AN: 1461892 Hom.: 27 Cov.: 33 AF XY: 0.00546 AC XY: 3973 AN XY: 727246

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00253 AC: 113 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00130 AC: 112 AN: 86258

European-Finnish (FIN) AF: 0.00286 AC: 153 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00661 AC: 7354 AN: 1112012

Other (OTH) AF: 0.00505 AC: 305 AN: 60396

GnomAD4 genome AF: 0.00382 AC: 582 AN: 152280 Hom.: 3 Cov.: 32 AF XY: 0.00361 AC XY: 269 AN XY: 74472

African (AFR) AF: 0.00125 AC: 52 AN: 41570

American (AMR) AF: 0.00307 AC: 47 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00625 AC: 425 AN: 68004

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00496 Hom.: 2

Bravo AF: 0.00358

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00346 AC: 420

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary spastic paraplegia 33 (4)
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.025
Sift	Benign	0.15	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.15
ClinPred		0.017	T
GERP RS		4.1
Varity_R		0.048
gMVP		0.20
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: rs140812293; hg19: chr10-99498296; COSMIC: COSV99047258;