rs764312409

Variant names:

• chr19-10984266-G-A
• rs764312409
• NM_001387283.1:c.115G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10984266-G-A
• chr19-10984266-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001387283.1(SMARCA4):​c.115G>A​(p.Ala39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,610,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A39V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.24
• Publications: 7 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15781692).
• BP6: Variant 19-10984266-G-A is Benign according to our data. Variant chr19-10984266-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408710.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000263 (4/152152) while in subpopulation AMR AF = 0.000196 (3/15280). AF 95% confidence interval is 0.0000529. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. 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.115G>A	p.Ala39Thr	missense	Exon 2 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.115G>A	p.Ala39Thr	missense	Exon 2 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.115G>A	p.Ala39Thr	missense	Exon 2 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.115G>A	p.Ala39Thr	missense	Exon 2 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.115G>A	p.Ala39Thr	missense	Exon 2 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.115G>A	p.Ala39Thr	missense	Exon 2 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000838 AC: 20 AN: 238588 AF XY: 0.0000919

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000471

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1458738 Hom.: 0 Cov.: 33 AF XY: 0.0000662 AC XY: 48 AN XY: 725546

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.000495 AC: 22 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85882

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111050

Other (OTH) AF: 0.0000166 AC: 1 AN: 60206

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.22
Sift	Benign	0.039	D
Sift4G	Benign	0.21	T
Polyphen		0.38	B
Vest4		0.15
MVP		0.59
MPC		0.25
ClinPred		0.049	T
GERP RS		3.9
PromoterAI		-0.051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.033
gMVP		0.063
Mutation Taster		=82/18	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: rs764312409; hg19: chr19-11094942;