19-46838377-C-T

Variant names:

• chr19-46838377-C-T
• rs76955283
• NM_004069.6:c.*70G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004069.6(AP2S1):​c.*70G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,506,520 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: AP2S1 NM_004069.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05
• Publications: 1 publications found

Genes affected

AP2S1 (HGNC:565): (adaptor related protein complex 2 subunit sigma 1) One of two major clathrin-associated adaptor complexes, AP-2, is a heterotetramer which is associated with the plasma membrane. This complex is composed of two large chains, a medium chain, and a small chain. This gene encodes the small chain of this complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

AP2S1 Gene-Disease associations (from GenCC):

• familial hypocalciuric hypercalcemia 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-46838377-C-T is Benign according to our data. Variant chr19-46838377-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1215661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1694/152226) while in subpopulation AFR AF = 0.039 (1619/41540). AF 95% confidence interval is 0.0374. There are 28 homozygotes in GnomAd4. There are 778 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1694 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004069.6. 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
	AP2S1	NM_004069.6	MANE Select	c.*70G>A		3_prime_UTR	Exon 5 of 5	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.*70G>A		3_prime_UTR	Exon 5 of 5	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.*70G>A		3_prime_UTR	Exon 5 of 5	NP_001288007.1	X6R390

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2S1	ENST00000263270.11	TSL:1 MANE Select	c.*70G>A		3_prime_UTR	Exon 5 of 5	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.*70G>A		3_prime_UTR	Exon 4 of 4	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000600964.1	TSL:1	n.253G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1684 AN: 152108 Hom.: 28 Cov.: 31

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00117 AC: 1578 AN: 1354294 Hom.: 35 Cov.: 21 AF XY: 0.000966 AC XY: 655 AN XY: 677874

African (AFR) AF: 0.0405 AC: 1259 AN: 31060

American (AMR) AF: 0.00220 AC: 94 AN: 42736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25292

East Asian (EAS) AF: 0.00 AC: 0 AN: 38578

South Asian (SAS) AF: 0.0000843 AC: 7 AN: 83004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51814

Middle Eastern (MID) AF: 0.00236 AC: 13 AN: 5516

European-Non Finnish (NFE) AF: 0.0000441 AC: 45 AN: 1019566

Other (OTH) AF: 0.00282 AC: 160 AN: 56728

GnomAD4 genome AF: 0.0111 AC: 1694 AN: 152226 Hom.: 28 Cov.: 31 AF XY: 0.0105 AC XY: 778 AN XY: 74432

African (AFR) AF: 0.0390 AC: 1619 AN: 41540

American (AMR) AF: 0.00360 AC: 55 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67988

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00899 Hom.: 2

Bravo AF: 0.0121

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.6
DANN	Benign	0.87
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs76955283; hg19: chr19-47341634;