11-34890551-C-T

Position:

• chr11-34890551-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015957.4(APIP):​c.160G>A​(p.Asp54Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,609,366 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: APIP NM_015957.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002875
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.533

Genes affected

APIP (HGNC:17581): (APAF1 interacting protein) Enables identical protein binding activity; methylthioribulose 1-phosphate dehydratase activity; and zinc ion binding activity. Involved in several processes, including L-methionine salvage from methylthioadenosine; protein homotetramerization; and pyroptosis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01780817).
• BP6: Variant 11-34890551-C-T is Benign according to our data. Variant chr11-34890551-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3127823.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APIP	NM_015957.4	c.160G>A	p.Asp54Asn	missense_variant, splice_region_variant	3/7	ENST00000395787.4
APIP	XM_011520154.4	c.211G>A	p.Asp71Asn	missense_variant, splice_region_variant	4/8
APIP	XM_017017875.3	c.-57G>A		splice_region_variant, 5_prime_UTR_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APIP	ENST00000395787.4	c.160G>A	p.Asp54Asn	missense_variant, splice_region_variant	3/7	1	NM_015957.4	P1
APIP	ENST00000532428.6	c.19G>A	p.Asp7Asn	missense_variant, NMD_transcript_variant	1/8	1
APIP	ENST00000527830.1	n.126G>A		splice_region_variant, non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000125 AC: 31 AN: 248448 Hom.: 0 AF XY: 0.000134 AC XY: 18 AN XY: 134378

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.0000597

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000146 AC: 213 AN: 1457144 Hom.: 2 Cov.: 30 AF XY: 0.000163 AC XY: 118 AN XY: 724812

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.0000904

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74416

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000329

EpiControl AF: 0.000298

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	0.61	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.053
Sift	Benign	0.38	T
Sift4G	Benign	0.50	T
Polyphen		0.018	B
Vest4		0.28
MVP		0.23
MPC		0.31
ClinPred		0.021	T
GERP RS		0.41
Varity_R		0.15
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		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: rs138989118; hg19: chr11-34912098;