chr14-50560111-C-G

Variant names:

• chr14-50560111-C-G
• rs886050530
• ENST00000441560.6:c.-139-16C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127713.1(ATL1):​c.-139-16C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 672,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ATL1 NM_001127713.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.504
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127713.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	NM_001127713.1		c.-139-16C>G		intron	N/A	NP_001121185.1	Q53F53
	ATL1	NM_015915.5	MANE Select	c.-155C>G		upstream_gene	N/A	NP_056999.2
	ATL1	NM_181598.4		c.-155C>G		upstream_gene	N/A	NP_853629.2	Q8WXF7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	ENST00000441560.6	TSL:1	c.-139-16C>G		intron	N/A	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000682037.1		c.-155C>G		5_prime_UTR	Exon 1 of 14	ENSP00000508289.1	A0A804HLC1
	ATL1	ENST00000868186.1		c.-155C>G		5_prime_UTR	Exon 1 of 13	ENSP00000538245.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 1 AN: 672470 Hom.: 0 Cov.: 9 AF XY: 0.00000285 AC XY: 1 AN XY: 350990

African (AFR) AF: 0.00 AC: 0 AN: 17682

American (AMR) AF: 0.00 AC: 0 AN: 31638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18368

East Asian (EAS) AF: 0.00 AC: 0 AN: 32016

South Asian (SAS) AF: 0.00 AC: 0 AN: 59278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3090

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 436576

Other (OTH) AF: 0.0000296 AC: 1 AN: 33828

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.55
PhyloP100		-0.50
PromoterAI		-0.034	Neutral

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: rs886050530; hg19: chr14-51026829;