rs3783408

Variant names:

• chr14-50533475-C-T
• rs3783408
• ENST00000441560.6:c.-140+108C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000441560.6(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 ENST00000441560.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ATL1	NM_001127713.1	c.-140+108C>T		intron_variant	Intron 1 of 13		NP_001121185.1
MAP4K5	XM_047430893.1	c.-109-1317G>A		intron_variant	Intron 2 of 33		XP_047286849.1
MAP4K5	XM_047430897.1	c.-109-1317G>A		intron_variant	Intron 2 of 32		XP_047286853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000441560.6	c.-140+108C>T		intron_variant	Intron 1 of 13	1		ENSP00000413675.2
ATL1	ENST00000556478.3	c.-140+602C>T		intron_variant	Intron 1 of 13	2		ENSP00000501428.2
ATL1	ENST00000713928.1	c.-140+529C>T		intron_variant	Intron 1 of 13			ENSP00000519225.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.0562 AC: 2331 AN: 41486

American (AMR) AF: 0.200 AC: 3050 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3470

East Asian (EAS) AF: 0.176 AC: 909 AN: 5166

South Asian (SAS) AF: 0.244 AC: 1176 AN: 4818

European-Finnish (FIN) AF: 0.254 AC: 2675 AN: 10546

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18974 AN: 67950

Other (OTH) AF: 0.231 AC: 488 AN: 2114

Alfa AF: 0.256 Hom.: 2861

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.58
PhyloP100		-0.029
PromoterAI		-0.017	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3783408; hg19: chr14-51000193;