NM_001283.5:c.4-11A>G

Variant names:

• chr7-101156583-A-G
• rs146333094
• NM_001283.5:c.4-11A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001283.5(AP1S1):​c.4-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000588 in 1,608,464 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (5 hom.)
• Consequence: AP1S1 NM_001283.5 intron
• Scores: Splicing: ADA: 0.00002844
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.166
• Publications: 1 publications found

Genes affected

AP1S1 (HGNC:559): (adaptor related protein complex 1 subunit sigma 1) The protein encoded by this gene is part of the clathrin coat assembly complex which links clathrin to receptors in coated vesicles. These vesicles are involved in endocytosis and Golgi processing. This protein, as well as beta-prime-adaptin, gamma-adaptin, and the medium (mu) chain AP47, form the AP-1 assembly protein complex located at the Golgi vesicle. [provided by RefSeq, Jul 2008]

AP1S1 Gene-Disease associations (from GenCC):

• MEDNIK syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Orphanet, Illumina

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-101156583-A-G is Benign according to our data. Variant chr7-101156583-A-G is described in ClinVar as Benign. ClinVar VariationId is 1600626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000834 (127/152274) while in subpopulation EAS AF = 0.0199 (103/5178). AF 95% confidence interval is 0.0168. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283.5. 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
	AP1S1	NM_001283.5	MANE Select	c.4-11A>G		intron	N/A	NP_001274.1	P61966-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1S1	ENST00000337619.11	TSL:1 MANE Select	c.4-11A>G		intron	N/A	ENSP00000336666.5	P61966-1
	AP1S1	ENST00000429457.1	TSL:5	c.127-11A>G		intron	N/A	ENSP00000399902.1	H7C1E4
	AP1S1	ENST00000926144.1		c.4-11A>G		intron	N/A	ENSP00000596203.1

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00151 AC: 367 AN: 242950 AF XY: 0.00150

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0172

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000453

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000562 AC: 819 AN: 1456190 Hom.: 5 Cov.: 30 AF XY: 0.000623 AC XY: 451 AN XY: 723530

African (AFR) AF: 0.000180 AC: 6 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.0141 AC: 557 AN: 39530

South Asian (SAS) AF: 0.00199 AC: 169 AN: 84986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1108974

Other (OTH) AF: 0.000980 AC: 59 AN: 60192

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74454

African (AFR) AF: 0.000120 AC: 5 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5178

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000816

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.48
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.010
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: rs146333094; hg19: chr7-100799864;