12-50086319-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003076.5(SMARCD1):c.336G>T(p.Gln112His) variant causes a missense change. The variant allele was found at a frequency of 0.00352 in 1,560,100 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (7 hom.)
• Consequence: SMARCD1 NM_003076.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.20

Genes affected

SMARCD1 (HGNC:11106): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 1) The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which 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 and has sequence similarity to the yeast Swp73 protein. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.010879189).
• BP6: Variant 12-50086319-G-T is Benign according to our data. Variant chr12-50086319-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2642976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00247 (372/150528) while in subpopulation NFE AF= 0.00447 (302/67502). AF 95% confidence interval is 0.00406. There are 0 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 372 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCD1	NM_003076.5	c.336G>T	p.Gln112His	missense_variant	2/13	ENST00000394963.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCD1	ENST00000394963.9	c.336G>T	p.Gln112His	missense_variant	2/13	1	NM_003076.5	P1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 372 AN: 150412 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000607

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000428

Gnomad FIN AF: 0.00158

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00279 AC: 672 AN: 241002 Hom.: 2 AF XY: 0.00276 AC XY: 361 AN XY: 130582

Gnomad AFR exome AF: 0.000935

Gnomad AMR exome AF: 0.000527

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00133

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00363 AC: 5114 AN: 1409572 Hom.: 7 Cov.: 33 AF XY: 0.00356 AC XY: 2498 AN XY: 701032

Gnomad4 AFR exome AF: 0.000782

Gnomad4 AMR exome AF: 0.000650

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00434

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00247 AC: 372 AN: 150528 Hom.: 0 Cov.: 31 AF XY: 0.00232 AC XY: 171 AN XY: 73616

Gnomad4 AFR AF: 0.000605

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.00233

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000428

Gnomad4 FIN AF: 0.00158

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00371 Hom.: 3

Bravo AF: 0.00233

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Coffin-Siris syndrome 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

European Non-Finnish population allele frequency is 0.4668% (rs139120093, 627/124688 alleles, 2 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

SMARCD1: PP2, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.091	T;.;T;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.010	D;D;T;D;T
Sift4G	Uncertain	0.028	D;D;D;D;D
Polyphen		0.010	B;D;.;.;.
Vest4		0.60
MutPred		0.35		Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);.;
MVP		0.72
MPC		1.0
ClinPred		0.040	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs139120093; hg19: chr12-50480102;