NM_001253852.3:c.38T>C

Variant names:

• chr1-113904680-A-G
• NM_001253852.3:c.38T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001253852.3(AP4B1):​c.38T>C​(p.Leu13Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP4B1 NM_001253852.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92
• Publications: 0 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]

DCLRE1B (HGNC:17641): (DNA cross-link repair 1B) DNA interstrand cross-links prevent strand separation, thereby physically blocking transcription, replication, and segregation of DNA. DCLRE1B is one of several evolutionarily conserved genes involved in repair of interstrand cross-links (Dronkert et al., 2000 [PubMed 10848582]).[supplied by OMIM, Mar 2008]

DCLRE1B Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal recessive 8

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

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.38T>C	p.Leu13Pro	missense	Exon 1 of 10	NP_001240781.1	Q9Y6B7-1
	AP4B1	NM_001438373.1		c.38T>C	p.Leu13Pro	missense	Exon 2 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.38T>C	p.Leu13Pro	missense	Exon 2 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.38T>C	p.Leu13Pro	missense	Exon 1 of 10	ENSP00000358582.1	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.38T>C	p.Leu13Pro	missense	Exon 2 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.38T>C	p.Leu13Pro	missense	Exon 1 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.083	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.83		Gain of disorder (P = 0.0126)
MVP		0.93
MPC		0.73
ClinPred		0.96	D
GERP RS		5.3
PromoterAI		-0.0032	Neutral
Varity_R		0.99
gMVP		0.86
Mutation Taster		=21/79	disease causing

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

hg19: chr1-114447302;