NM_003076.5:c.365A>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003076.5(SMARCD1):c.365A>C(p.Asn122Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 815,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N122S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

SMARCD1
NM_003076.5 missense, splice_region

Scores

Splicing: ADA: 0.002846

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.34

Publications

0 publications found

Variant links:

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]

SMARCD1 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome 11
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
Coffin-Siris syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SMARCD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14194122).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003076.5. 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
	SMARCD1	NM_003076.5	MANE Select	c.365A>C	p.Asn122Thr	missense splice_region	Exon 2 of 13	NP_003067.3
	SMARCD1	NM_139071.3		c.365A>C	p.Asn122Thr	missense splice_region	Exon 2 of 12	NP_620710.2	Q96GM5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCD1	ENST00000394963.9	TSL:1 MANE Select	c.365A>C	p.Asn122Thr	missense splice_region	Exon 2 of 13	ENSP00000378414.4	Q96GM5-1
SMARCD1	ENST00000381513.8	TSL:1	c.365A>C	p.Asn122Thr	missense splice_region	Exon 2 of 12	ENSP00000370924.4	Q96GM5-2
SMARCD1	ENST00000547247.5	TSL:1	n.393A>C		splice_region non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000245

AC:

AN:

815310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

415416

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000532

AC:

AN:

18790

American (AMR)

AF:

0.00

AC:

AN:

34260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13310

East Asian (EAS)

AF:

0.00

AC:

AN:

16692

South Asian (SAS)

AF:

0.00

AC:

AN:

71974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3594

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

592844

Other (OTH)

AF:

0.0000322

AC:

AN:

31068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.058

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.062

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

3.3

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.36

REVEL

Benign

0.055

Sift

Benign

0.27

Sift4G

Benign

0.53

Polyphen

0.0050

Vest4

0.31

MutPred

0.36

Gain of phosphorylation at N122 (P = 0.0389)

MVP

0.17

MPC

1.1

ClinPred

0.78

GERP RS

4.9

Varity_R

0.084

gMVP

0.47

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0028

dbscSNV1_RF

Benign

0.094

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over