rs174765

Variant names:

• chr22-29331877-C-T
• rs174765
• NM_001127.4:c.2349G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-29331877-C-T
• chr22-29331877-C-A
• chr22-29331877-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127.4(AP1B1):​c.2349G>A​(p.Ala783Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,612,808 control chromosomes in the GnomAD database, including 251,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20796 hom., cov: 32)
  • Exomes 𝑓: 0.56 (230254 hom.)
• Consequence: AP1B1 NM_001127.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.15
• Publications: 25 publications found

Genes affected

AP1B1 (HGNC:554): (adaptor related protein complex 1 subunit beta 1) Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as one of the large subunits of this complex and is a member of the adaptin protein family. This gene is a candidate meningioma gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

AP1B1 Gene-Disease associations (from GenCC):

• ichthyosiform erythroderma, corneal involvement, and hearing loss

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P, ClinGen
• MEDNIK syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 22-29331877-C-T is Benign according to our data. Variant chr22-29331877-C-T is described in ClinVar as Benign. ClinVar VariationId is 1192401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127.4. 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
	AP1B1	NM_001127.4	MANE Select	c.2349G>A	p.Ala783Ala	synonymous	Exon 18 of 23	NP_001118.3
	AP1B1	NM_001378562.1		c.2349G>A	p.Ala783Ala	synonymous	Exon 18 of 22	NP_001365491.1
	AP1B1	NM_001378563.1		c.2328G>A	p.Ala776Ala	synonymous	Exon 17 of 22	NP_001365492.1	Q10567-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1B1	ENST00000357586.7	TSL:1 MANE Select	c.2349G>A	p.Ala783Ala	synonymous	Exon 18 of 23	ENSP00000350199.2	Q10567-1
	AP1B1	ENST00000317368.11	TSL:1	c.2268G>A	p.Ala756Ala	synonymous	Exon 17 of 21	ENSP00000319361.7	Q10567-4
	AP1B1	ENST00000482818.1	TSL:1	n.445G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78908 AN: 151814 Hom.: 20777 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.526

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.522

GnomAD2 exomes AF: 0.539 AC: 134695 AN: 249986 AF XY: 0.541

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.455

Gnomad ASJ exome AF: 0.489

Gnomad EAS exome AF: 0.697

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.559 AC: 816519 AN: 1460876 Hom.: 230254 Cov.: 45 AF XY: 0.557 AC XY: 404566 AN XY: 726732

African (AFR) AF: 0.446 AC: 14931 AN: 33458

American (AMR) AF: 0.451 AC: 20154 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12840 AN: 26126

East Asian (EAS) AF: 0.684 AC: 27169 AN: 39694

South Asian (SAS) AF: 0.513 AC: 44266 AN: 86242

European-Finnish (FIN) AF: 0.581 AC: 30840 AN: 53120

Middle Eastern (MID) AF: 0.489 AC: 2817 AN: 5760

European-Non Finnish (NFE) AF: 0.568 AC: 630869 AN: 1111424

Other (OTH) AF: 0.541 AC: 32633 AN: 60358

GnomAD4 genome AF: 0.520 AC: 78969 AN: 151932 Hom.: 20796 Cov.: 32 AF XY: 0.519 AC XY: 38501 AN XY: 74246

African (AFR) AF: 0.449 AC: 18599 AN: 41458

American (AMR) AF: 0.455 AC: 6962 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1745 AN: 3464

East Asian (EAS) AF: 0.682 AC: 3509 AN: 5146

South Asian (SAS) AF: 0.526 AC: 2526 AN: 4802

European-Finnish (FIN) AF: 0.583 AC: 6159 AN: 10572

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.556 AC: 37718 AN: 67894

Other (OTH) AF: 0.528 AC: 1112 AN: 2108

Alfa AF: 0.518 Hom.: 13590

Bravo AF: 0.509

Asia WGS AF: 0.618 AC: 2152 AN: 3478

EpiCase AF: 0.548

EpiControl AF: 0.547

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive keratitis-ichthyosis-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.68
DANN	Benign	0.72
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs174765; hg19: chr22-29727866; COSMIC: COSV58014221; COSMIC: COSV58014221;