rs374894037

Variant names:

• chr1-113898739-G-A
• rs374894037
• NM_001253852.3:c.1177C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-113898739-G-A
• chr1-113898739-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001253852.3(AP4B1):​c.1177C>T​(p.Arg393*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,609,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R393R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AP4B1 NM_001253852.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.09
• Publications: 2 publications found

Genes affected

AP4B1 (HGNC:572): (adaptor related protein complex 4 subunit beta 1) This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

AP4B1-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-113898739-G-A is Pathogenic according to our data. Variant chr1-113898739-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 539527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001253852.3. 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
	AP4B1	NM_001253852.3	MANE Select	c.1177C>T	p.Arg393*	stop_gained	Exon 6 of 10	NP_001240781.1	Q9Y6B7-1
	AP4B1	NM_001438373.1		c.1177C>T	p.Arg393*	stop_gained	Exon 7 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.1177C>T	p.Arg393*	stop_gained	Exon 7 of 11	NP_006585.2	Q9Y6B7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4B1	ENST00000369569.6	TSL:1 MANE Select	c.1177C>T	p.Arg393*	stop_gained	Exon 6 of 10	ENSP00000358582.1	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.1177C>T	p.Arg393*	stop_gained	Exon 7 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.1303C>T	p.Arg435*	stop_gained	Exon 7 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000479

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247150 AF XY: 0.00

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457520 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725260

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111950

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74222

African (AFR) AF: 0.0000725 AC: 3 AN: 41358

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.0000782 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary spastic paraplegia 47 (5)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		3.1
Vest4		0.41
GERP RS		4.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374894037; hg19: chr1-114441361; COSMIC: COSV108019675; COSMIC: COSV108019675;