3-40182315-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015460.4(MYRIP):c.969C>A(p.His323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,614,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: MYRIP NM_015460.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59

Genes affected

MYRIP (HGNC:19156): (myosin VIIA and Rab interacting protein) Predicted to enable actin binding activity and myosin binding activity. Predicted to be involved in positive regulation of insulin secretion. Predicted to be located in actin cytoskeleton; dense core granule; and perinuclear region of cytoplasm. Predicted to be part of exocyst. Predicted to be active in cortical actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

EIF1B-AS1 (HGNC:44555): (EIF1B antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008208424).
• BP6: Variant 3-40182315-C-A is Benign according to our data. Variant chr3-40182315-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3169843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRIP	NM_015460.4	c.969C>A	p.His323Gln	missense_variant	9/17	ENST00000302541.11
EIF1B-AS1	NR_033965.1	n.537-7593G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRIP	ENST00000302541.11	c.969C>A	p.His323Gln	missense_variant	9/17	1	NM_015460.4	P1
EIF1B-AS1	ENST00000657703.1	n.91-64579G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.000456

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000311 AC: 78 AN: 251078 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135706

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000343 AC: 501 AN: 1461708 Hom.: 1 Cov.: 31 AF XY: 0.000345 AC XY: 251 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000395

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74480

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000392 Hom.: 1

Bravo AF: 0.000672

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.035
Dann	Benign	0.67
DEOGEN2	Benign	0.015	T;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.018
MutPred		0.096		Gain of glycosylation at S328 (P = 0.037);Gain of glycosylation at S328 (P = 0.037);.;Gain of glycosylation at S328 (P = 0.037);.;
MVP		0.25
MPC		0.10
ClinPred		0.0048	T
GERP RS		-4.5
Varity_R		0.058
gMVP		0.064

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: rs140013771; hg19: chr3-40223806;