chr10-97738539-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001385875.1(ZFYVE27):​c.62C>A​(p.Ala21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZFYVE27 NM_001385875.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13399121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE27	NM_001385875.1	c.62C>A	p.Ala21Asp	missense_variant	Exon 2 of 13	ENST00000684270.1	NP_001372804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE27	ENST00000684270.1	c.62C>A	p.Ala21Asp	missense_variant	Exon 2 of 13		NM_001385875.1	ENSP00000506975.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62C>A (p.A21D) alteration is located in exon 1 (coding exon 1) of the ZFYVE27 gene. This alteration results from a C to A substitution at nucleotide position 62, causing the alanine (A) at amino acid position 21 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0055	.;.;.;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.063
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	T;T;D;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L
PhyloP100		2.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.76	N;N;N;N;.;N
REVEL	Benign	0.059
Sift	Benign	0.037	D;D;D;D;.;D
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.73, 0.38, 0.13	.;.;P;B;P;B
Vest4		0.65
MutPred		0.11		Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);
MVP		0.28
ClinPred		0.60	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.26
Mutation Taster		=93/7	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;