NM_020159.5:c.412A>G

Variant names:

• chr4-94233997-A-G
• rs149019191
• NM_020159.5:c.412A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020159.5(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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M138I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (5 hom.)
• Consequence: SMARCAD1 NM_020159.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0110
• Publications: 2 publications found

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]

SMARCAD1 Gene-Disease associations (from GenCC):

• ectodermal dysplasia syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• isolated congenital adermatoglyphia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• palmoplantar keratoderma-sclerodactyly syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P
• absence of fingerprints-congenital milia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 229 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020159.5. 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
	SMARCAD1	NM_020159.5	MANE Select	c.412A>G	p.Met138Val	missense	Exon 4 of 24	NP_064544.2	Q9H4L7-1
	SMARCAD1	NM_001128429.3		c.412A>G	p.Met138Val	missense	Exon 4 of 24	NP_001121901.1	Q9H4L7-2
	SMARCAD1	NM_001128430.2		c.412A>G	p.Met138Val	missense	Exon 4 of 24	NP_001121902.1	Q9H4L7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAD1	ENST00000354268.9	TSL:1 MANE Select	c.412A>G	p.Met138Val	missense	Exon 4 of 24	ENSP00000346217.4	Q9H4L7-1
	SMARCAD1	ENST00000359052.8	TSL:1	c.412A>G	p.Met138Val	missense	Exon 4 of 24	ENSP00000351947.4	Q9H4L7-2
	SMARCAD1	ENST00000457823.6	TSL:1	c.412A>G	p.Met138Val	missense	Exon 4 of 24	ENSP00000415576.2	Q9H4L7-2

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

GnomAD2 exomes AF: 0.000443 AC: 110 AN: 248578 AF XY: 0.000320

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 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

African (AFR) AF: 0.00541 AC: 181 AN: 33458

American (AMR) AF: 0.000336 AC: 15 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39652

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111768

Other (OTH) AF: 0.000530 AC: 32 AN: 60368

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

African (AFR) AF: 0.00515 AC: 214 AN: 41580

American (AMR) AF: 0.000523 AC: 8 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000581 Hom.: 1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.011
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.0080
Sift	Benign	1.0	T
Sift4G	Benign	0.50	T
Polyphen		0.0	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
Mutation Taster		=97/3	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: rs149019191; hg19: chr4-95155148;