chr19-10987745-C-T

Variant names:

• chr19-10987745-C-T
• rs755971351
• NM_001387283.1:c.939C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_003072.5(SMARCA4):​c.939C>T​(p.Pro313Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,449,588 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P313P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.31
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-10987745-C-T is Benign according to our data. Variant chr19-10987745-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 470470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000414 (60/1449588) while in subpopulation NFE AF = 0.0000506 (56/1106070). AF 95% confidence interval is 0.00004. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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.939C>T	p.Pro313Pro	synonymous	Exon 6 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.939C>T	p.Pro313Pro	synonymous	Exon 6 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.939C>T	p.Pro313Pro	synonymous	Exon 6 of 36	NP_001122321.1	Q9HBD4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.939C>T	p.Pro313Pro	synonymous	Exon 6 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.939C>T	p.Pro313Pro	synonymous	Exon 6 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.939C>T	p.Pro313Pro	synonymous	Exon 6 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000228 AC: 5 AN: 218914 AF XY: 0.0000249

Gnomad AFR exome AF: 0.0000793

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000321

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000414 AC: 60 AN: 1449588 Hom.: 0 Cov.: 33 AF XY: 0.0000389 AC XY: 28 AN XY: 720386

African (AFR) AF: 0.0000301 AC: 1 AN: 33172

American (AMR) AF: 0.0000228 AC: 1 AN: 43842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39114

South Asian (SAS) AF: 0.00 AC: 0 AN: 85172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000506 AC: 56 AN: 1106070

Other (OTH) AF: 0.0000167 AC: 1 AN: 59792

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000488 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (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	-0.77
CADD	Benign	0.89
DANN	Benign	0.70
PhyloP100		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs755971351; hg19: chr19-11098421;