19-10987920-T-C

Variant names:

• chr19-10987920-T-C
• rs140192268
• NM_001387283.1:c.1114T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128849.3(SMARCA4):​c.1114T>C​(p.Tyr372His) variant causes a missense change. The variant allele was found at a frequency of 0.0139 in 1,612,450 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y372N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 32)
  • Exomes 𝑓: 0.014 (206 hom.)
• Consequence: SMARCA4 NM_001128849.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 6.14
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008926064).
• BP6: Variant 19-10987920-T-C is Benign according to our data. Variant chr19-10987920-T-C is described in ClinVar as Benign. ClinVar VariationId is 126355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0101 (1541/152168) while in subpopulation AMR AF = 0.0153 (233/15272). AF 95% confidence interval is 0.0144. There are 11 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.1114T>C	p.Tyr372His	missense	Exon 6 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.1114T>C	p.Tyr372His	missense	Exon 6 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.1114T>C	p.Tyr372His	missense	Exon 6 of 36	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.1114T>C	p.Tyr372His	missense	Exon 6 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1114T>C	p.Tyr372His	missense	Exon 6 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.1114T>C	p.Tyr372His	missense	Exon 6 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1541 AN: 152050 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00329

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00961 AC: 2310 AN: 240404 AF XY: 0.00950

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00446

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0143 AC: 20822 AN: 1460282 Hom.: 206 Cov.: 34 AF XY: 0.0140 AC XY: 10145 AN XY: 726422

African (AFR) AF: 0.00257 AC: 86 AN: 33446

American (AMR) AF: 0.0126 AC: 561 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00261 AC: 225 AN: 86164

European-Finnish (FIN) AF: 0.00498 AC: 263 AN: 52840

Middle Eastern (MID) AF: 0.00761 AC: 39 AN: 5126

European-Non Finnish (NFE) AF: 0.0169 AC: 18832 AN: 1111910

Other (OTH) AF: 0.0128 AC: 770 AN: 60294

GnomAD4 genome AF: 0.0101 AC: 1541 AN: 152168 Hom.: 11 Cov.: 32 AF XY: 0.00949 AC XY: 706 AN XY: 74400

African (AFR) AF: 0.00328 AC: 136 AN: 41518

American (AMR) AF: 0.0153 AC: 233 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

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

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4812

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1034 AN: 67992

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0123 Hom.: 30

Bravo AF: 0.0110

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00278 AC: 12

ESP6500EA AF: 0.0152 AC: 127

ExAC AF: 0.00953 AC: 1153

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0167

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	3	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.039
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.45
Sift	Benign	0.49	T
Sift4G	Benign	0.53	T
Polyphen		0.040	B
Vest4		0.52
MVP		0.91
MPC		1.7
ClinPred		0.0091	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.84
Mutation Taster		=98/2	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: rs140192268; hg19: chr19-11098596; COSMIC: COSV99065485; COSMIC: COSV99065485;