4-94226402-C-T

Variant names:

• chr4-94226402-C-T
• rs72665660
• NM_020159.5:c.368+106C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_020159.5(SMARCAD1):​c.368+106C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (24 hom., cov: 18)
  • Exomes 𝑓: 0.038 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCAD1 NM_020159.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.31
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-94226402-C-T is Benign according to our data. Variant chr4-94226402-C-T is described in ClinVar as Benign. ClinVar VariationId is 1253074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.368+106C>T		intron	N/A	NP_064544.2	Q9H4L7-1
	SMARCAD1	NM_001128429.3		c.368+106C>T		intron	N/A	NP_001121901.1	Q9H4L7-2
	SMARCAD1	NM_001128430.2		c.368+106C>T		intron	N/A	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.368+106C>T		intron	N/A	ENSP00000346217.4	Q9H4L7-1
	SMARCAD1	ENST00000359052.8	TSL:1	c.368+106C>T		intron	N/A	ENSP00000351947.4	Q9H4L7-2
	SMARCAD1	ENST00000457823.6	TSL:1	c.368+106C>T		intron	N/A	ENSP00000415576.2	Q9H4L7-2

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 4208 AN: 122304 Hom.: 23 Cov.: 18

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.0255

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0440

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0509

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0304

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0382 AC: 12673 AN: 331916 Hom.: 2 AF XY: 0.0388 AC XY: 6898 AN XY: 177740

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

African (AFR) AF: 0.0533 AC: 435 AN: 8166

American (AMR) AF: 0.0442 AC: 515 AN: 11650

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 465 AN: 9472

East Asian (EAS) AF: 0.0357 AC: 700 AN: 19608

South Asian (SAS) AF: 0.0454 AC: 1411 AN: 31096

European-Finnish (FIN) AF: 0.0730 AC: 1485 AN: 20346

Middle Eastern (MID) AF: 0.0361 AC: 46 AN: 1276

European-Non Finnish (NFE) AF: 0.0327 AC: 6970 AN: 212974

Other (OTH) AF: 0.0373 AC: 646 AN: 17328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0345 AC: 4217 AN: 122306 Hom.: 24 Cov.: 18 AF XY: 0.0359 AC XY: 2056 AN XY: 57296

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

African (AFR) AF: 0.0481 AC: 1548 AN: 32156

American (AMR) AF: 0.0217 AC: 243 AN: 11210

Ashkenazi Jewish (ASJ) AF: 0.0440 AC: 139 AN: 3162

East Asian (EAS) AF: 0.0331 AC: 146 AN: 4408

South Asian (SAS) AF: 0.0169 AC: 68 AN: 4014

European-Finnish (FIN) AF: 0.0415 AC: 169 AN: 4072

Middle Eastern (MID) AF: 0.0556 AC: 11 AN: 198

European-Non Finnish (NFE) AF: 0.0300 AC: 1820 AN: 60576

Other (OTH) AF: 0.0308 AC: 52 AN: 1688

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.541 Hom.: 7609

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.19
DANN	Benign	0.19
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs72665660; hg19: chr4-95147553; COSMIC: COSV62773420;