rs3783408

Positions:

• chr14-50533475-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127713.1(ATL1):​c.-140+108C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,032 control chromosomes in the GnomAD database, including 3,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3868 hom., cov: 32)
  • Exomes 𝑓: 0.17 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATL1 NM_001127713.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290

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]

ATL1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-50533475-C-T is Benign according to our data. Variant chr14-50533475-C-T is described in ClinVar as [Benign]. Clinvar id is 1262528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_001127713.1	c.-140+108C>T		intron_variant			NP_001121185.1
MAP4K5	XM_047430893.1	c.-109-1317G>A		intron_variant			XP_047286849.1
MAP4K5	XM_047430897.1	c.-109-1317G>A		intron_variant			XP_047286853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000441560.6	c.-140+108C>T		intron_variant		1		ENSP00000413675.2
ATL1	ENST00000556478.3	c.-140+602C>T		intron_variant		2		ENSP00000501428.2
MAP4K5	ENST00000555216.5	c.-94+9024G>A		intron_variant		4		ENSP00000452289.1
ATL1	ENST00000682219.1	n.740+108C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30693 AN: 151914 Hom.: 3868 Cov.: 32

Gnomad AFR AF: 0.0563

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.231

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.167 AC: 1 AN: 6 Hom.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.202 AC: 30700 AN: 152032 Hom.: 3868 Cov.: 32 AF XY: 0.201 AC XY: 14907 AN XY: 74280

Gnomad4 AFR AF: 0.0562

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.279

Gnomad4 OTH AF: 0.231

Alfa AF: 0.257 Hom.: 2587

Bravo AF: 0.190

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.58

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3783408; hg19: chr14-51000193;