rs11172254

Variant names:

• chr12-57574955-G-A
• rs11172254
• NM_004984.4:c.1717-129G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57574955-G-A
• chr12-57574955-G-T

Variant summary

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

The NM_004984.4(KIF5A):​c.1717-129G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 801,012 control chromosomes in the GnomAD database, including 122,824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (18837 hom., cov: 31)
  • Exomes 𝑓: 0.55 (103987 hom.)
• Consequence: KIF5A NM_004984.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.753
• Publications: 27 publications found

Genes affected

KIF5A (HGNC:6323): (kinesin family member 5A) This gene encodes a member of the kinesin family of proteins. Members of this family are part of a multisubunit complex that functions as a microtubule motor in intracellular organelle transport. Mutations in this gene cause autosomal dominant spastic paraplegia 10. [provided by RefSeq, Jul 2008]

KIF5A Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis, susceptibility to, 25

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• inherited neurodegenerative disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• myoclonus, intractable, neonatal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 10

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation

  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=-0.89).
• BP6: Variant 12-57574955-G-A is Benign according to our data. Variant chr12-57574955-G-A is described in ClinVar as Benign. ClinVar VariationId is 682853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4	c.1717-129G>A		intron_variant	Intron 15 of 28	ENST00000455537.7	NP_004975.2
KIF5A	NM_001354705.2	c.1450-129G>A		intron_variant	Intron 12 of 25		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7	c.1717-129G>A		intron_variant	Intron 15 of 28	1	NM_004984.4	ENSP00000408979.2

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69944 AN: 151924 Hom.: 18846 Cov.: 31

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.518

GnomAD4 exome AF: 0.550 AC: 356700 AN: 648970 Hom.: 103987 AF XY: 0.547 AC XY: 188468 AN XY: 344808

African (AFR) AF: 0.177 AC: 3074 AN: 17414

American (AMR) AF: 0.470 AC: 16183 AN: 34406

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 12238 AN: 20138

East Asian (EAS) AF: 0.209 AC: 6840 AN: 32672

South Asian (SAS) AF: 0.411 AC: 26076 AN: 63376

European-Finnish (FIN) AF: 0.485 AC: 21528 AN: 44396

Middle Eastern (MID) AF: 0.619 AC: 1896 AN: 3064

European-Non Finnish (NFE) AF: 0.627 AC: 250842 AN: 399966

Other (OTH) AF: 0.537 AC: 18023 AN: 33538

GnomAD4 genome AF: 0.460 AC: 69922 AN: 152042 Hom.: 18837 Cov.: 31 AF XY: 0.452 AC XY: 33550 AN XY: 74286

African (AFR) AF: 0.185 AC: 7691 AN: 41472

American (AMR) AF: 0.508 AC: 7760 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2134 AN: 3468

East Asian (EAS) AF: 0.229 AC: 1183 AN: 5170

South Asian (SAS) AF: 0.393 AC: 1892 AN: 4818

European-Finnish (FIN) AF: 0.463 AC: 4884 AN: 10552

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42655 AN: 67974

Other (OTH) AF: 0.513 AC: 1082 AN: 2110

Alfa AF: 0.574 Hom.: 43622

Bravo AF: 0.450

Asia WGS AF: 0.312 AC: 1086 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 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.71
DANN	Benign	0.65
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs11172254; hg19: chr12-57968738; COSMIC: COSV54055337;