chr6-148440320-G-C

Variant names:

• chr6-148440320-G-C
• rs2272998
• NM_015278.5:c.337-38G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015278.5(SASH1):​c.337-38G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,611,128 control chromosomes in the GnomAD database, including 146,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13727 hom., cov: 30)
  • Exomes 𝑓: 0.42 (132404 hom.)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-148440320-G-C is Benign according to our data. Variant chr6-148440320-G-C is described in ClinVar as [Benign]. Clinvar id is 1289486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH1	NM_015278.5	c.337-38G>C		intron_variant	Intron 3 of 19	ENST00000367467.8	NP_056093.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH1	ENST00000367467.8	c.337-38G>C		intron_variant	Intron 3 of 19	1	NM_015278.5	ENSP00000356437.3
SASH1	ENST00000367469.5	n.255-38G>C		intron_variant	Intron 3 of 3	3
SASH1	ENST00000470750.1	n.-38G>C		upstream_gene_variant		3
SASH1	ENST00000637469.1	n.-59G>C		upstream_gene_variant		4		ENSP00000490499.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 63932 AN: 151476 Hom.: 13719 Cov.: 30

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.446 AC: 111954 AN: 251268 AF XY: 0.456

Gnomad AFR exome AF: 0.404

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.425

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.421 AC: 614296 AN: 1459534 Hom.: 132404 Cov.: 32 AF XY: 0.428 AC XY: 310633 AN XY: 726266

Gnomad4 AFR exome AF: 0.419 AC: 14015 AN: 33432

Gnomad4 AMR exome AF: 0.426 AC: 19056 AN: 44716

Gnomad4 ASJ exome AF: 0.426 AC: 11122 AN: 26128

Gnomad4 EAS exome AF: 0.409 AC: 16248 AN: 39680

Gnomad4 SAS exome AF: 0.663 AC: 57123 AN: 86218

Gnomad4 FIN exome AF: 0.460 AC: 24578 AN: 53416

Gnomad4 NFE exome AF: 0.400 AC: 444248 AN: 1109858

Gnomad4 Remaining exome AF: 0.423 AC: 25488 AN: 60318

GnomAD4 genome AF: 0.422 AC: 63970 AN: 151594 Hom.: 13727 Cov.: 30 AF XY: 0.430 AC XY: 31832 AN XY: 74048

Gnomad4 AFR AF: 0.418 AC: 0.418441 AN: 0.418441

Gnomad4 AMR AF: 0.403 AC: 0.403399 AN: 0.403399

Gnomad4 ASJ AF: 0.426 AC: 0.426054 AN: 0.426054

Gnomad4 EAS AF: 0.414 AC: 0.413645 AN: 0.413645

Gnomad4 SAS AF: 0.682 AC: 0.681799 AN: 0.681799

Gnomad4 FIN AF: 0.454 AC: 0.45367 AN: 0.45367

Gnomad4 NFE AF: 0.406 AC: 0.406035 AN: 0.406035

Gnomad4 OTH AF: 0.392 AC: 0.391698 AN: 0.391698

Alfa AF: 0.421 Hom.: 2462

Bravo AF: 0.410

Asia WGS AF: 0.538 AC: 1870 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyschromatosis universalis hereditaria 1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.59
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

Publications

LitVar

Other links and lift over

dbSNP: rs2272998; hg19: chr6-148761456; COSMIC: COSV66562149; COSMIC: COSV66562149;