6-130834904-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195597.2(SMLR1):c.273A>T(p.Gln91His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,383,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: SMLR1 NM_001195597.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0180

Genes affected

SMLR1 (HGNC:44670): (small leucine rich protein 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12228286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMLR1	NM_001195597.2	c.273A>T	p.Gln91His	missense_variant	2/2	ENST00000541421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMLR1	ENST00000541421.2	c.273A>T	p.Gln91His	missense_variant	2/2	1	NM_001195597.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000146 AC: 2 AN: 136536 Hom.: 0 AF XY: 0.0000135 AC XY: 1 AN XY: 74126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000365

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000868 AC: 12 AN: 1383098 Hom.: 0 Cov.: 30 AF XY: 0.00000586 AC XY: 4 AN XY: 682506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.273A>T (p.Q91H) alteration is located in exon 2 (coding exon 2) of the SMLR1 gene. This alteration results from a A to T substitution at nucleotide position 273, causing the glutamine (Q) at amino acid position 91 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.9
Dann	Benign	0.81
DEOGEN2	Benign	0.055	T
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.12	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.5	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.019	D
Vest4		0.093
MVP		0.055
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.048

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: rs1184742806; hg19: chr6-131156044;