6-148440226-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015278.5(SASH1):c.328C>G(p.Gln110Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00134 in 1,614,052 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts 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. Q110P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (18 hom., cov: 31)
  • Exomes 𝑓: 0.00074 (10 hom.)
• Consequence: SASH1 NM_015278.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.43

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008813471).
• BP6: Variant 6-148440226-C-G is Benign according to our data. Variant chr6-148440226-C-G is described in ClinVar as [Benign]. Clinvar id is 716141.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00706 (1074/152194) while in subpopulation AFR AF= 0.0245 (1019/41532). AF 95% confidence interval is 0.0233. There are 18 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SASH1	NM_015278.5	c.328C>G	p.Gln110Glu	missense_variant	3/20	ENST00000367467.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SASH1	ENST00000367467.8	c.328C>G	p.Gln110Glu	missense_variant	3/20	1	NM_015278.5	P1
SASH1	ENST00000367469.5	n.246C>G		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 1076 AN: 152076 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00183 AC: 461 AN: 251432 Hom.: 10 AF XY: 0.00132 AC XY: 179 AN XY: 135892

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000742 AC: 1085 AN: 1461858 Hom.: 10 Cov.: 31 AF XY: 0.000667 AC XY: 485 AN XY: 727226

Gnomad4 AFR exome AF: 0.0260

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00706 AC: 1074 AN: 152194 Hom.: 18 Cov.: 31 AF XY: 0.00721 AC XY: 536 AN XY: 74392

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00122 Hom.: 1

Bravo AF: 0.00817

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Benign	0.88
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.27	N
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.19
Sift	Benign	0.22	T
Sift4G	Benign	1.0	T
Polyphen		0.98	D
Vest4		0.72
MVP		0.59
MPC		0.21
ClinPred		0.033	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.085

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34521137; hg19: chr6-148761362;