4-94233997-A-G

Position:

• chr4-94233997-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The ENST00000354268.9(SMARCAD1):​c.412A>G​(p.Met138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,780 control chromosomes in the GnomAD database, including 5 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (5 hom.)
• Consequence: SMARCAD1 ENST00000354268.9 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0110

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 -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCAD1. . Gene score misZ 3.492 (greater than the threshold 3.09). Trascript score misZ 4.2048 (greater than threshold 3.09). GenCC has associacion of gene with absence of fingerprints-congenital milia syndrome, ectodermal dysplasia syndrome, isolated congenital adermatoglyphia, palmoplantar keratoderma-sclerodactyly syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036287904).
• BP6: Variant 4-94233997-A-G is Benign according to our data. Variant chr4-94233997-A-G is described in ClinVar as [Benign]. Clinvar id is 731092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0015 (229/152298) while in subpopulation AFR AF= 0.00515 (214/41580). AF 95% confidence interval is 0.00458. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCAD1	NM_020159.5	c.412A>G	p.Met138Val	missense_variant	4/24	ENST00000354268.9	NP_064544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCAD1	ENST00000354268.9	c.412A>G	p.Met138Val	missense_variant	4/24	1	NM_020159.5	ENSP00000346217	P4

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000443 AC: 110 AN: 248578 Hom.: 0 AF XY: 0.000320 AC XY: 43 AN XY: 134536

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 243 AN: 1461482 Hom.: 5 Cov.: 31 AF XY: 0.000143 AC XY: 104 AN XY: 727032

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74480

Gnomad4 AFR AF: 0.00515

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.00155

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.096
DANN	Benign	0.35
DEOGEN2	Benign	0.076	.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.48	.;T;T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.20	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.19	N;N;N
REVEL	Benign	0.0080
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.098
MVP		0.18
MPC		0.31
ClinPred		0.0012	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033

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: rs149019191; hg19: chr4-95155148;