19-11003321-G-T

Variant names:

• chr19-11003321-G-T
• rs74942410
• NM_001387283.1:c.1944-19G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003072.5(SMARCA4):​c.1944-19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 1,611,630 control chromosomes in the GnomAD database, including 3,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (317 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3673 hom.)
• Consequence: SMARCA4 NM_003072.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0440
• Publications: 13 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=-0.84).
• BP6: Variant 19-11003321-G-T is Benign according to our data. Variant chr19-11003321-G-T is described in ClinVar as Benign. ClinVar VariationId is 257530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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.1944-19G>T		intron	N/A	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.1944-19G>T		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.1944-19G>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.1944-19G>T		intron	N/A	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1944-19G>T		intron	N/A	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.1944-19G>T		intron	N/A	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.0612 AC: 9307 AN: 152144 Hom.: 318 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0779

Gnomad EAS AF: 0.0338

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0933

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0694

GnomAD2 exomes AF: 0.0657 AC: 16526 AN: 251468 AF XY: 0.0695

Gnomad AFR exome AF: 0.0520

Gnomad AMR exome AF: 0.0309

Gnomad ASJ exome AF: 0.0702

Gnomad EAS exome AF: 0.0335

Gnomad FIN exome AF: 0.0880

Gnomad NFE exome AF: 0.0660

Gnomad OTH exome AF: 0.0721

GnomAD4 exome AF: 0.0670 AC: 97803 AN: 1459368 Hom.: 3673 Cov.: 31 AF XY: 0.0686 AC XY: 49797 AN XY: 726172

African (AFR) AF: 0.0528 AC: 1766 AN: 33442

American (AMR) AF: 0.0332 AC: 1483 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0719 AC: 1878 AN: 26120

East Asian (EAS) AF: 0.0271 AC: 1077 AN: 39686

South Asian (SAS) AF: 0.110 AC: 9502 AN: 86204

European-Finnish (FIN) AF: 0.0887 AC: 4737 AN: 53414

Middle Eastern (MID) AF: 0.0753 AC: 434 AN: 5766

European-Non Finnish (NFE) AF: 0.0657 AC: 72860 AN: 1109702

Other (OTH) AF: 0.0674 AC: 4066 AN: 60312

GnomAD4 genome AF: 0.0612 AC: 9320 AN: 152262 Hom.: 317 Cov.: 32 AF XY: 0.0632 AC XY: 4704 AN XY: 74462

African (AFR) AF: 0.0532 AC: 2212 AN: 41556

American (AMR) AF: 0.0375 AC: 573 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0779 AC: 270 AN: 3468

East Asian (EAS) AF: 0.0341 AC: 177 AN: 5190

South Asian (SAS) AF: 0.112 AC: 540 AN: 4832

European-Finnish (FIN) AF: 0.0933 AC: 990 AN: 10606

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0641 AC: 4356 AN: 67998

Other (OTH) AF: 0.0705 AC: 149 AN: 2112

Alfa AF: 0.0408 Hom.: 41

Bravo AF: 0.0560

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.33
PhyloP100		0.044
PromoterAI		0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs74942410; hg19: chr19-11113997; COSMIC: COSV60798617;