chr14-50632151-A-G

Variant names:

• chr14-50632151-A-G
• rs113367786
• ENST00000555720.5:c.*2002T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000555720.5(SAV1):​c.*2002T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 858,970 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (11 hom.)
• Consequence: SAV1 ENST00000555720.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00100
• Publications: 0 publications found

Genes affected

SAV1 (HGNC:17795): (salvador family WW domain containing protein 1) WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein with two WW domains, a SARAH domain, and a coiled-coil region and is ubiquitously expressed in adult tissues. This protein binds to MST1 (mammalian sterile 20-like kinase 1) and promotes MST1-induced apoptosis. It has also been shown to bind to HAX1 (hematopoietic cell-specific protein 1 (HS1)-associated protein X-1) and to attenuate the anti-apoptotic effects of HAX1. Studies in human and mouse suggest this gene acts as a tumor suppressor. [provided by RefSeq, Aug 2012]

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]

ATL1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 3A

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• neuropathy, hereditary sensory, type 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-50632151-A-G is Benign according to our data. Variant chr14-50632151-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1204485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1626/152336) while in subpopulation AFR AF = 0.0357 (1485/41570). AF 95% confidence interval is 0.0342. There are 26 homozygotes in GnomAd4. There are 794 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1626 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000555720.5. 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.1567-78A>G		intron	N/A	NP_056999.2
	ATL1	NM_001127713.1		c.1552-78A>G		intron	N/A	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.1552-78A>G		intron	N/A	NP_853629.2	Q8WXF7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAV1	ENST00000555720.5	TSL:1	c.*2002T>C		3_prime_UTR	Exon 5 of 5	ENSP00000451492.1	H0YJH0
	ATL1	ENST00000358385.12	TSL:1 MANE Select	c.1567-78A>G		intron	N/A	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.1552-78A>G		intron	N/A	ENSP00000413675.2	Q8WXF7-2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1622 AN: 152218 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00107 AC: 757 AN: 706634 Hom.: 11 Cov.: 9 AF XY: 0.000847 AC XY: 315 AN XY: 371864

African (AFR) AF: 0.0339 AC: 557 AN: 16452

American (AMR) AF: 0.00211 AC: 58 AN: 27522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18636

East Asian (EAS) AF: 0.00 AC: 0 AN: 32464

South Asian (SAS) AF: 0.0000172 AC: 1 AN: 58200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47864

Middle Eastern (MID) AF: 0.00144 AC: 5 AN: 3468

European-Non Finnish (NFE) AF: 0.0000812 AC: 38 AN: 467742

Other (OTH) AF: 0.00286 AC: 98 AN: 34286

GnomAD4 genome AF: 0.0107 AC: 1626 AN: 152336 Hom.: 26 Cov.: 32 AF XY: 0.0107 AC XY: 794 AN XY: 74494

African (AFR) AF: 0.0357 AC: 1485 AN: 41570

American (AMR) AF: 0.00693 AC: 106 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00541 Hom.: 2

Bravo AF: 0.0122

Asia WGS AF: 0.00289 AC: 10 AN: 3474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.82
DANN	Benign	0.42
PhyloP100		0.0010
Mutation Taster		=100/0	polymorphism

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: rs113367786; hg19: chr14-51098869;