14-50533422-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000441560.6(ATL1):c.-140+55A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 152,204 control chromosomes in the GnomAD database, including 75,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.99 (75183 hom., cov: 30)
  • Exomes 𝑓: 1.0 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATL1 ENST00000441560.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.28

Genes affected

ATL1 (HGNC:11231): (atlastin GTPase 1) The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MAP4K5 (HGNC:6867): (mitogen-activated protein kinase kinase kinase kinase 5) This gene encodes a member of the serine/threonine protein kinase family, that is highly similar to yeast SPS1/STE20 kinase. Yeast SPS1/STE20 functions near the beginning of the MAP kinase signal cascades that is essential for yeast pheromone response. This kinase was shown to activate Jun kinase in mammalian cells, which suggested a role in stress response. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-50533422-A-T is Benign according to our data. Variant chr14-50533422-A-T is described in ClinVar as [Benign]. Clinvar id is 678056.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL1	NM_001127713.1	c.-140+55A>T		intron_variant
MAP4K5	XM_047430893.1	c.-109-1264T>A		intron_variant
MAP4K5	XM_047430897.1	c.-109-1264T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL1	ENST00000441560.6	c.-140+55A>T		intron_variant		1		A1
MAP4K5	ENST00000555216.5	c.-94+9077T>A		intron_variant		4
ATL1	ENST00000556478.3	c.-140+549A>T		intron_variant		2		A1
ATL1	ENST00000682219.1	n.740+55A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.994 AC: 151155 AN: 152086 Hom.: 75126 Cov.: 30

Gnomad AFR AF: 0.978

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.998

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 1.00 AC: 4 AN: 4 Hom.: 2 AF XY: 1.00 AC XY: 4 AN XY: 4

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.994 AC: 151271 AN: 152204 Hom.: 75183 Cov.: 30 AF XY: 0.994 AC XY: 73982 AN XY: 74404

Gnomad4 AFR AF: 0.978

Gnomad4 AMR AF: 0.998

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.998

Alfa AF: 0.997 Hom.: 8615

Bravo AF: 0.993

Asia WGS AF: 0.999 AC: 3475 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	7.1
Dann	Benign	0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7152509; hg19: chr14-51000140;