rs757097521

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-35870936-C-G
• chr19-35870936-C-A
• chr19-35870936-C-T

Variant summary

Our verdict is Likely benign. The variant received -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. 14/21 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
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024807.3. 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
	APLP1	NM_001024807.3	MANE Select	c.332C>G	p.Thr111Arg	missense	Exon 3 of 17	NP_001019978.1	P51693-2
	APLP1	NM_005166.5		c.332C>G	p.Thr111Arg	missense	Exon 3 of 17	NP_005157.1	P51693-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP1	ENST00000221891.9	TSL:1 MANE Select	c.332C>G	p.Thr111Arg	missense	Exon 3 of 17	ENSP00000221891.4	P51693-2
	APLP1	ENST00000960045.1		c.332C>G	p.Thr111Arg	missense	Exon 3 of 18	ENSP00000630104.1
	APLP1	ENST00000898023.1		c.332C>G	p.Thr111Arg	missense	Exon 3 of 17	ENSP00000568082.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000179 AC: 4 AN: 222940 AF XY: 0.00000833

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.0000944 AC: 4 AN: 42382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25678

East Asian (EAS) AF: 0.000331 AC: 13 AN: 39242

South Asian (SAS) AF: 0.00 AC: 0 AN: 83234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106824

Other (OTH) AF: 0.00 AC: 0 AN: 59852

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.019	D
Polyphen		0.26	B
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
PromoterAI		-0.019	Neutral
gMVP		0.40
Mutation Taster		=87/13	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: rs757097521; hg19: chr19-36361838;