6-148343146-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_015278.5(SASH1):c.79C>G(p.Pro27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 1,598,850 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: SASH1 NM_015278.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0620

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008150458).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000618 (94/152204) while in subpopulation NFE AF= 0.001 (68/67980). AF 95% confidence interval is 0.000809. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SASH1	NM_015278.5	c.79C>G	p.Pro27Ala	missense_variant	1/20	ENST00000367467.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SASH1	ENST00000367467.8	c.79C>G	p.Pro27Ala	missense_variant	1/20	1	NM_015278.5	P1
SASH1	ENST00000367469.5	n.75-46988C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000586 AC: 135 AN: 230294 Hom.: 0 AF XY: 0.000567 AC XY: 72 AN XY: 127076

Gnomad AFR exome AF: 0.0000693

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000164

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000864

GnomAD4 exome AF: 0.000965 AC: 1396 AN: 1446646 Hom.: 1 Cov.: 31 AF XY: 0.000943 AC XY: 679 AN XY: 720044

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000223

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.000915

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74424

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000646 Hom.: 0

Bravo AF: 0.000759

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000816 AC: 7

ExAC AF: 0.000638 AC: 77

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.79C>G (p.P27A) alteration is located in exon 1 (coding exon 1) of the SASH1 gene. This alteration results from a C to G substitution at nucleotide position 79, causing the proline (P) at amino acid position 27 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	11
Dann	Benign	0.64
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.076	T
Polyphen		0.015	B
Vest4		0.17
MVP		0.16
MPC		0.14
ClinPred		0.011	T
GERP RS		2.0
Varity_R		0.054
gMVP		0.15

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: rs200427643; hg19: chr6-148664282; COSMIC: COSV105302998;