19-10987787-A-C

Variant names:

• chr19-10987787-A-C
• rs547268941
• NM_001387283.1:c.981A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001128849.3(SMARCA4):​c.981A>C​(p.Pro327Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,599,206 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P327P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (12 hom.)
• Consequence: SMARCA4 NM_001128849.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.61
• Publications: 4 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: ClinGen, Orphanet, 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: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-10987787-A-C is Benign according to our data. Variant chr19-10987787-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00241 (362/150178) while in subpopulation SAS AF = 0.00383 (18/4698). AF 95% confidence interval is 0.00248. There are 1 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128849.3. 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.981A>C	p.Pro327Pro	synonymous	Exon 6 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.981A>C	p.Pro327Pro	synonymous	Exon 6 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.981A>C	p.Pro327Pro	synonymous	Exon 6 of 36	NP_001122321.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.981A>C	p.Pro327Pro	synonymous	Exon 6 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.981A>C	p.Pro327Pro	synonymous	Exon 6 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.981A>C	p.Pro327Pro	synonymous	Exon 6 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 362 AN: 150062 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.0345

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00383

Gnomad FIN AF: 0.000876

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00261

Gnomad OTH AF: 0.000966

GnomAD2 exomes AF: 0.00300 AC: 643 AN: 214150 AF XY: 0.00302

Gnomad AFR exome AF: 0.000167

Gnomad AMR exome AF: 0.000930

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000423

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.00227

GnomAD4 exome AF: 0.00293 AC: 4247 AN: 1449028 Hom.: 12 Cov.: 34 AF XY: 0.00294 AC XY: 2116 AN XY: 719890

African (AFR) AF: 0.000271 AC: 9 AN: 33168

American (AMR) AF: 0.00104 AC: 45 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 754 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39118

South Asian (SAS) AF: 0.00394 AC: 335 AN: 84936

European-Finnish (FIN) AF: 0.000691 AC: 35 AN: 50618

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5638

European-Non Finnish (NFE) AF: 0.00258 AC: 2854 AN: 1106688

Other (OTH) AF: 0.00358 AC: 214 AN: 59746

GnomAD4 genome AF: 0.00241 AC: 362 AN: 150178 Hom.: 1 Cov.: 32 AF XY: 0.00202 AC XY: 148 AN XY: 73276

African (AFR) AF: 0.000464 AC: 19 AN: 40926

American (AMR) AF: 0.00126 AC: 19 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 119 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5084

South Asian (SAS) AF: 0.00383 AC: 18 AN: 4698

European-Finnish (FIN) AF: 0.000876 AC: 9 AN: 10278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00261 AC: 176 AN: 67324

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.00515 Hom.: 1

Bravo AF: 0.00222

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Coffin-Siris syndrome (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Intellectual disability, autosomal dominant 16 (1)
-	-	1	Rhabdoid tumor predisposition syndrome 2 (1)
-	-	1	SMARCA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.44
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs547268941; hg19: chr19-11098463; COSMIC: COSV60786023;