6-148390546-A-G

Variant names:

• chr6-148390546-A-G
• rs7774517
• NM_015278.5:c.285+284A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015278.5(SASH1):​c.285+284A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,132 control chromosomes in the GnomAD database, including 43,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.75 (43012 hom., cov: 32)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.440
• Publications: 0 publications found

Genes affected

SASH1 (HGNC:19182): (SAM and SH3 domain containing 1) This gene encodes a scaffold protein involved in the TLR4 signaling pathway that may stimulate cytokine production and endothelial cell migration in response to invading pathogens. The encoded protein has also been described as a potential tumor suppressor that may negatively regulate proliferation, apoptosis, and invasion of cancer cells, and reduced expression of this gene has been observed in multiple human cancers. Mutations in this gene may be associated with abnormal skin pigmentation in human patients. [provided by RefSeq, Oct 2016]

SASH1 Gene-Disease associations (from GenCC):

• dyschromatosis universalis hereditaria 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• familial generalized lentiginosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 6-148390546-A-G is Benign according to our data. Variant chr6-148390546-A-G is described in ClinVar as Benign. ClinVar VariationId is 1269216.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015278.5. 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
	SASH1	NM_015278.5	MANE Select	c.285+284A>G		intron	N/A	NP_056093.3
	SASH1	NM_001346505.2		c.150+284A>G		intron	N/A	NP_001333434.1
	SASH1	NM_001346506.2		c.-153+284A>G		intron	N/A	NP_001333435.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH1	ENST00000367467.8	TSL:1 MANE Select	c.285+284A>G		intron	N/A	ENSP00000356437.3	O94885
	SASH1	ENST00000946242.1		c.285+284A>G		intron	N/A	ENSP00000616301.1
	SASH1	ENST00000946243.1		c.285+284A>G		intron	N/A	ENSP00000616302.1

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113934 AN: 152014 Hom.: 42971 Cov.: 32

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.812

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.742

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.749 AC: 114019 AN: 152132 Hom.: 43012 Cov.: 32 AF XY: 0.749 AC XY: 55693 AN XY: 74362

African (AFR) AF: 0.800 AC: 33203 AN: 41518

American (AMR) AF: 0.814 AC: 12441 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2646 AN: 3472

East Asian (EAS) AF: 0.546 AC: 2826 AN: 5178

South Asian (SAS) AF: 0.838 AC: 4042 AN: 4822

European-Finnish (FIN) AF: 0.709 AC: 7493 AN: 10574

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48868 AN: 67976

Other (OTH) AF: 0.734 AC: 1546 AN: 2106

Alfa AF: 0.730 Hom.: 5047

Bravo AF: 0.756

Asia WGS AF: 0.666 AC: 2321 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism (auto)

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: rs7774517; hg19: chr6-148711682;