19-10987010-T-A

Variant names:

• chr19-10987010-T-A
• rs141461778
• NM_001387283.1:c.859+7T>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_003072.5(SMARCA4):​c.859+7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,595,254 control chromosomes in the GnomAD database, including 27 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 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (24 hom.)
• Consequence: SMARCA4 NM_003072.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001071
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.67
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-10987010-T-A is Benign according to our data. Variant chr19-10987010-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00178 (271/152246) while in subpopulation SAS AF = 0.0135 (65/4830). AF 95% confidence interval is 0.0108. There are 3 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,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.859+7T>A		splice_region intron	N/A	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.859+7T>A		splice_region intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.859+7T>A		splice_region 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.859+7T>A		splice_region intron	N/A	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.859+7T>A		splice_region intron	N/A	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.859+7T>A		splice_region intron	N/A	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152128 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00370 AC: 891 AN: 240966 AF XY: 0.00449

Gnomad AFR exome AF: 0.0000633

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000886

Gnomad OTH exome AF: 0.00417

GnomAD4 exome AF: 0.00211 AC: 3045 AN: 1443008 Hom.: 24 Cov.: 30 AF XY: 0.00260 AC XY: 1868 AN XY: 718690

African (AFR) AF: 0.000360 AC: 12 AN: 33330

American (AMR) AF: 0.00148 AC: 66 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 723 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0141 AC: 1211 AN: 86018

European-Finnish (FIN) AF: 0.000116 AC: 5 AN: 42952

Middle Eastern (MID) AF: 0.00679 AC: 39 AN: 5744

European-Non Finnish (NFE) AF: 0.000705 AC: 779 AN: 1104572

Other (OTH) AF: 0.00350 AC: 210 AN: 60004

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152246 Hom.: 3 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74434

African (AFR) AF: 0.000217 AC: 9 AN: 41554

American (AMR) AF: 0.00177 AC: 27 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00503 Hom.: 2

Bravo AF: 0.00161

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00125

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Coffin-Siris syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colon cancer (1)
-	-	1	Intellectual disability, autosomal dominant 16 (1)
-	-	1	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.49
DANN	Benign	0.50
PhyloP100		-1.7
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	0.000011
dbscSNV1_RF	Benign	0.0060
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: rs141461778; hg19: chr19-11097686; COSMIC: COSV60791609;