rs7439869

chr4-94252628-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_020159.5(SMARCAD1):c.902T>C(p.Val301Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,554,320 control chromosomes in the GnomAD database, including 298,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.69 (37826 hom., cov: 33)
  • Exomes 𝑓: 0.61 (260805 hom.)
• Consequence: SMARCAD1 NM_020159.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.58

Genes affected

SMARCAD1 (HGNC:18398): (SWI/SNF-related, matrix-associated actin-dependent regulator of chromatin, subfamily a, containing DEAD/H box 1) This gene encodes a member of the SNF subfamily of helicase proteins. The encoded protein plays a critical role in the restoration of heterochromatin organization and propagation of epigenetic patterns following DNA replication by mediating histone H3/H4 deacetylation. Mutations in this gene are associated with adermatoglyphia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCAD1
• BP4: Computational evidence support a benign effect (MetaRNN=5.577926E-7).
• BP6: Variant 4-94252628-T-C is Benign according to our data. Variant chr4-94252628-T-C is described in ClinVar as [Benign]. Clinvar id is 1220932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-94252628-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAD1	NM_020159.5	c.902T>C	p.Val301Ala	missense_variant	9/24	ENST00000354268.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAD1	ENST00000354268.9	c.902T>C	p.Val301Ala	missense_variant	9/24	1	NM_020159.5	P4

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105108 AN: 151948 Hom.: 37769 Cov.: 33

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.648

GnomAD3 exomes AF: 0.638 AC: 125256 AN: 196308 Hom.: 40898 AF XY: 0.628 AC XY: 66942 AN XY: 106656

Gnomad AFR exome AF: 0.913

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.709

Gnomad SAS exome AF: 0.641

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.606

GnomAD4 exome AF: 0.606 AC: 849279 AN: 1402254 Hom.: 260805 Cov.: 31 AF XY: 0.605 AC XY: 420843 AN XY: 695456

Gnomad4 AFR exome AF: 0.919

Gnomad4 AMR exome AF: 0.732

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.759

Gnomad4 SAS exome AF: 0.641

Gnomad4 FIN exome AF: 0.577

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.617

GnomAD4 genome AF: 0.692 AC: 105228 AN: 152066 Hom.: 37826 Cov.: 33 AF XY: 0.693 AC XY: 51499 AN XY: 74330

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.690

Gnomad4 ASJ AF: 0.564

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.644

Gnomad4 FIN AF: 0.572

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.654

Alfa AF: 0.609 Hom.: 60666

Bravo AF: 0.712

TwinsUK AF: 0.581 AC: 2153

ALSPAC AF: 0.573 AC: 2207

ESP6500AA AF: 0.909 AC: 3962

ESP6500EA AF: 0.596 AC: 5093

ExAC AF: 0.627 AC: 75263

Asia WGS AF: 0.701 AC: 2434 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Keratoderma with scleroatrophy of the extremities Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Basan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 29874175) -

Adermatoglyphia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	15
Dann	Benign	0.17
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0036	N
MetaRNN	Benign	5.6e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.68	N;N;N
REVEL	Benign	0.070
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.81	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.020
MPC		0.36
ClinPred		0.0023	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017

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: rs7439869; hg19: chr4-95173779; COSMIC: COSV62772953; COSMIC: COSV62772953;