2-241073367-G-A

Position:

• chr2-241073367-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080437.3(SNED1):​c.3916+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,563,294 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: SNED1 NM_001080437.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001542
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.149

Genes affected

SNED1 (HGNC:24696): (sushi, nidogen and EGF like domains 1) Predicted to enable Notch binding activity. Predicted to be involved in cell-matrix adhesion. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

SNED1 (HGNC:):

MTERF4 (HGNC:28785): (mitochondrial transcription termination factor 4) Enables rRNA binding activity. Predicted to be involved in rRNA processing and regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including mitochondrial transcription; protein targeting to mitochondrion; and ribosome assembly. Located in cytosol and mitochondrion. Part of mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028863847).
• BP6: Variant 2-241073367-G-A is Benign according to our data. Variant chr2-241073367-G-A is described in ClinVar as [Benign]. Clinvar id is 717178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00972 (1481/152346) while in subpopulation AFR AF= 0.0329 (1368/41578). AF 95% confidence interval is 0.0315. There are 21 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNED1	NM_001080437.3	c.3916+3G>A		splice_region_variant, intron_variant		ENST00000310397.13	NP_001073906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNED1	ENST00000310397.13	c.3916+3G>A		splice_region_variant, intron_variant		5	NM_001080437.3	ENSP00000308893.8

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1479 AN: 152228 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00241 AC: 407 AN: 168684 Hom.: 6 AF XY: 0.00180 AC XY: 162 AN XY: 89930

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000430

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00107 AC: 1516 AN: 1410948 Hom.: 24 Cov.: 29 AF XY: 0.000954 AC XY: 665 AN XY: 697226

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.00292

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000501

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000911

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00972 AC: 1481 AN: 152346 Hom.: 21 Cov.: 32 AF XY: 0.00949 AC XY: 707 AN XY: 74490

Gnomad4 AFR AF: 0.0329

Gnomad4 AMR AF: 0.00522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00506 Hom.: 6

Bravo AF: 0.0116

ESP6500AA AF: 0.0284 AC: 118

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00183 AC: 208

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.3
DANN	Benign	0.79
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.84	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.14
Sift	Benign	0.41	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.16
ClinPred		0.0034	T
GERP RS		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs6721364; hg19: chr2-242012782;