19-35870936-C-G

Variant names:

• chr19-35870936-C-G
• rs757097521
• NM_001024807.3:c.332C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001024807.3(APLP1):​c.332C>G​(p.Thr111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,448,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: APLP1 NM_001024807.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

APLP1 (HGNC:597): (amyloid beta precursor like protein 1) This gene encodes a member of the highly conserved amyloid precursor protein gene family. The encoded protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 precursor protein cleavage. This cleavage liberates an intracellular cytoplasmic fragment that may act as a transcriptional activator. The encoded protein may also play a role in synaptic maturation during cortical development. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23325947).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APLP1	NM_001024807.3	c.332C>G	p.Thr111Arg	missense_variant	Exon 3 of 17	ENST00000221891.9	NP_001019978.1
APLP1	NM_005166.5	c.332C>G	p.Thr111Arg	missense_variant	Exon 3 of 17		NP_005157.1
APLP1	XM_017026737.3	c.332C>G	p.Thr111Arg	missense_variant	Exon 3 of 16		XP_016882226.1
APLP1	XM_017026738.3	c.332C>G	p.Thr111Arg	missense_variant	Exon 3 of 16		XP_016882227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APLP1	ENST00000221891.9	c.332C>G	p.Thr111Arg	missense_variant	Exon 3 of 17	1	NM_001024807.3	ENSP00000221891.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000179 AC: 4 AN: 222940 Hom.: 0 AF XY: 0.00000833 AC XY: 1 AN XY: 120034

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000117 AC: 17 AN: 1448200 Hom.: 0 Cov.: 31 AF XY: 0.00000974 AC XY: 7 AN XY: 718790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000944

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.332C>G (p.T111R) alteration is located in exon 3 (coding exon 3) of the APLP1 gene. This alteration results from a C to G substitution at nucleotide position 332, causing the threonine (T) at amino acid position 111 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T;.;.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	1.1	.;L;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.94	N;N;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D;D;.;.;.
Sift4G	Uncertain	0.019	D;D;D;T;T
Polyphen		0.26	B;B;P;.;.
Vest4		0.30
MutPred		0.54		.;Gain of MoRF binding (P = 0.019);.;.;.;
MVP		0.71
MPC		0.46
ClinPred		0.19	T
GERP RS		2.6
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs757097521; hg19: chr19-36361838;