11-77900570-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS2

The ENST00000304716.12(AAMDC):c.329-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 672,104 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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 0.0017 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: AAMDC ENST00000304716.12 splice_acceptor
• Scores: Splicing: ADA: 0.00002975
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.317

Genes affected

AAMDC (HGNC:30205): (adipogenesis associated Mth938 domain containing) Predicted to be involved in positive regulation of fat cell differentiation. Predicted to act upstream of or within negative regulation of apoptotic process and positive regulation of transcription by RNA polymerase II. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

INTS4 (HGNC:25048): (integrator complex subunit 4) INTS4 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.32207206 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of -45, new splice context is: agtatgtttctgtgtttaAGcat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 11-77900570-G-A is Benign according to our data. Variant chr11-77900570-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2642194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INTS4	NM_033547.4	c.2228+851C>T		intron_variant		ENST00000534064.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INTS4	ENST00000534064.6	c.2228+851C>T		intron_variant		1	NM_033547.4	P3

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 262 AN: 151086 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000309 AC: 34 AN: 109994 Hom.: 0 AF XY: 0.000249 AC XY: 15 AN XY: 60270

Gnomad AFR exome AF: 0.00539

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.000196 AC: 102 AN: 520908 Hom.: 0 Cov.: 0 AF XY: 0.000166 AC XY: 47 AN XY: 282824

Gnomad4 AFR exome AF: 0.00570

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000651

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.00175 AC: 264 AN: 151196 Hom.: 4 Cov.: 32 AF XY: 0.00161 AC XY: 119 AN XY: 73770

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00226

ExAC AF: 0.000409 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

AAMDC: BS2; INTS4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.91
Cadd	Benign	13
Dann	Benign	0.58
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.0028	N
MutationTaster	Benign	1.0	N;N;N;N;N
GERP RS		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs377187803; hg19: chr11-77611616;