4-94253672-G-T

Variant names:

• chr4-94253672-G-T
• rs1057519613
• NM_020159.5:c.1281+665G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001375859.1(SMARCAD1):​c.-10+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCAD1 NM_001375859.1 splice_donor, intron
• Scores: Splicing: ADA: 0.8492
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.31
• 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: G2P, Orphanet
• absence of fingerprints-congenital milia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.20200334 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of -23, new splice context is: tagGTgaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-94253672-G-T is Pathogenic according to our data. Variant chr4-94253672-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30981.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375859.1. 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.1281+665G>T		intron	N/A	NP_064544.2
	SMARCAD1	NM_001128429.3		c.1281+665G>T		intron	N/A	NP_001121901.1
	SMARCAD1	NM_001128430.2		c.1281+665G>T		intron	N/A	NP_001121902.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAD1	ENST00000354268.9	TSL:1 MANE Select	c.1281+665G>T		intron	N/A	ENSP00000346217.4
	SMARCAD1	ENST00000359052.8	TSL:1	c.1281+665G>T		intron	N/A	ENSP00000351947.4
	SMARCAD1	ENST00000457823.6	TSL:1	c.1281+665G>T		intron	N/A	ENSP00000415576.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Adermatoglyphia (1)
1	-	-	Basan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Uncertain	0.99
PhyloP100		6.3
PromoterAI		-0.21	Neutral
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.64
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: rs1057519613; hg19: chr4-95174823;