rs180832203

Variant names:

• chr19-10984391-C-T
• rs180832203
• NM_001387283.1:c.222+18C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10984391-C-T
• chr19-10984391-C-A
• chr19-10984391-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003072.5(SMARCA4):​c.222+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,562,620 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (34 hom.)
• Consequence: SMARCA4 NM_003072.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.63
• Publications: 1 publications found

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• otosclerosis

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-10984391-C-T is Benign according to our data. Variant chr19-10984391-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 380632.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00398 (607/152352) while in subpopulation SAS AF = 0.0108 (52/4832). AF 95% confidence interval is 0.00843. There are 3 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003072.5. 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
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.222+18C>T		intron	N/A	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.222+18C>T		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.222+18C>T		intron	N/A	NP_001122321.1	Q9HBD4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.222+18C>T		intron	N/A	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.222+18C>T		intron	N/A	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.222+18C>T		intron	N/A	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 608 AN: 152234 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00455 AC: 752 AN: 165184 AF XY: 0.00511

Gnomad AFR exome AF: 0.000647

Gnomad AMR exome AF: 0.000949

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00634

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00437

GnomAD4 exome AF: 0.00519 AC: 7322 AN: 1410268 Hom.: 34 Cov.: 33 AF XY: 0.00542 AC XY: 3777 AN XY: 696952

African (AFR) AF: 0.000564 AC: 18 AN: 31926

American (AMR) AF: 0.00146 AC: 55 AN: 37736

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 31 AN: 25270

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36426

South Asian (SAS) AF: 0.0106 AC: 853 AN: 80408

European-Finnish (FIN) AF: 0.00716 AC: 352 AN: 49144

Middle Eastern (MID) AF: 0.00589 AC: 32 AN: 5430

European-Non Finnish (NFE) AF: 0.00530 AC: 5753 AN: 1085522

Other (OTH) AF: 0.00389 AC: 227 AN: 58406

GnomAD4 genome AF: 0.00398 AC: 607 AN: 152352 Hom.: 3 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74506

African (AFR) AF: 0.000890 AC: 37 AN: 41588

American (AMR) AF: 0.00216 AC: 33 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4832

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00579 AC: 394 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00427 Hom.: 1

Bravo AF: 0.00297

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)
-	-	1	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.72
PhyloP100		-1.6
PromoterAI		0.030	Neutral
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: rs180832203; hg19: chr19-11095067; COSMIC: COSV104653913;