chr14-67786202-A-G

Variant names:

• chr14-67786202-A-G
• rs138895639
• NM_015346.4:c.3051T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015346.4(ZFYVE26):​c.3051T>C​(p.Ala1017Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,603,192 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.712
• Publications: 1 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), Orphanet, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-67786202-A-G is Benign according to our data. Variant chr14-67786202-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448889.
• BP7: Synonymous conserved (PhyloP=0.712 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000648 (96/148190) while in subpopulation AMR AF = 0.00268 (38/14196). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.3051T>C	p.Ala1017Ala	synonymous	Exon 17 of 42	NP_056161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.3051T>C	p.Ala1017Ala	synonymous	Exon 17 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.3051T>C	p.Ala1017Ala	synonymous	Exon 17 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.3188T>C		non_coding_transcript_exon	Exon 17 of 41

Frequencies

GnomAD3 genomes AF: 0.000648 AC: 96 AN: 148078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00232

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000577

Gnomad OTH AF: 0.00245

GnomAD2 exomes AF: 0.000708 AC: 178 AN: 251446 AF XY: 0.000706

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000500 AC: 728 AN: 1455002 Hom.: 2 Cov.: 38 AF XY: 0.000496 AC XY: 359 AN XY: 723806

African (AFR) AF: 0.000331 AC: 11 AN: 33274

American (AMR) AF: 0.00166 AC: 74 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00340 AC: 88 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 38744

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00400 AC: 23 AN: 5744

European-Non Finnish (NFE) AF: 0.000418 AC: 463 AN: 1107780

Other (OTH) AF: 0.00105 AC: 63 AN: 59960

GnomAD4 genome AF: 0.000648 AC: 96 AN: 148190 Hom.: 0 Cov.: 32 AF XY: 0.000487 AC XY: 35 AN XY: 71822

African (AFR) AF: 0.0000988 AC: 4 AN: 40506

American (AMR) AF: 0.00268 AC: 38 AN: 14196

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 8 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 4884

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9662

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.000577 AC: 39 AN: 67546

Other (OTH) AF: 0.00243 AC: 5 AN: 2060

Alfa AF: 0.000982 Hom.: 1

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.5
DANN	Benign	0.66
PhyloP100		0.71
Mutation Taster		=99/1	polymorphism

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: rs138895639; hg19: chr14-68252919;