rs146613929

Variant names:

• chr14-50560295-T-C
• rs146613929
• NM_015915.5:c.30T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015915.5(ATL1):​c.30T>C​(p.Ser10Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,762 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: ATL1 NM_015915.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.189
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 14-50560295-T-C is Benign according to our data. Variant chr14-50560295-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.189 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000657 (100/152154) while in subpopulation AFR AF = 0.00214 (89/41504). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 100 AD,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015915.5. 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_015915.5	MANE Select	c.30T>C	p.Ser10Ser	synonymous	Exon 1 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.30T>C	p.Ser10Ser	synonymous	Exon 2 of 14	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.30T>C	p.Ser10Ser	synonymous	Exon 1 of 13	NP_853629.2	Q8WXF7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	ENST00000358385.12	TSL:1 MANE Select	c.30T>C	p.Ser10Ser	synonymous	Exon 1 of 14	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.30T>C	p.Ser10Ser	synonymous	Exon 2 of 14	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000557735.2	TSL:4	c.-421T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000451015.2	G3V334

Frequencies

GnomAD3 genomes AF: 0.000658 AC: 100 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000221 AC: 55 AN: 249240 AF XY: 0.000111

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461608 Hom.: 0 Cov.: 30 AF XY: 0.0000646 AC XY: 47 AN XY: 727122

African (AFR) AF: 0.00263 AC: 88 AN: 33464

American (AMR) AF: 0.000403 AC: 18 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111846

Other (OTH) AF: 0.000133 AC: 8 AN: 60376

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74398

African (AFR) AF: 0.00214 AC: 89 AN: 41504

American (AMR) AF: 0.000588 AC: 9 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67972

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.000858

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 3A (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuropathy, hereditary sensory, type 1D (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		-0.19
PromoterAI		-0.018	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: rs146613929; hg19: chr14-51027013;