22-43964455-G-A

Position:

• chr22-43964455-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000350028.5(SAMM50):​c.136G>A​(p.Val46Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00339 in 1,587,678 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: SAMM50 ENST00000350028.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.64

Genes affected

SAMM50 (HGNC:24276): (SAMM50 sorting and assembly machinery component) This gene encodes a component of the Sorting and Assembly Machinery (SAM) of the mitochondrial outer membrane. The Sam complex functions in the assembly of beta-barrel proteins into the outer mitochondrial membrane.[provided by RefSeq, Jun 2011]

PNPLA3 (HGNC:18590): (patatin like phospholipase domain containing 3) The protein encoded by this gene is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes. The encoded protein, which appears to be membrane bound, may be involved in the balance of energy usage/storage in adipocytes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013418645).
• BP6: Variant 22-43964455-G-A is Benign according to our data. Variant chr22-43964455-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 714564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMM50	NM_015380.5	c.136G>A	p.Val46Ile	missense_variant	3/15	ENST00000350028.5	NP_056195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMM50	ENST00000350028.5	c.136G>A	p.Val46Ile	missense_variant	3/15	1	NM_015380.5	ENSP00000345445	P1
SAMM50	ENST00000493161.1	n.318G>A		non_coding_transcript_exon_variant	3/7	3
PNPLA3	ENST00000406117.6	c.*964G>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	2		ENSP00000384668

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152132 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00180 AC: 452 AN: 250866 Hom.: 3 AF XY: 0.00171 AC XY: 232 AN XY: 135586

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00352 AC: 5052 AN: 1435428 Hom.: 11 Cov.: 26 AF XY: 0.00342 AC XY: 2447 AN XY: 715464

Gnomad4 AFR exome AF: 0.000606

Gnomad4 AMR exome AF: 0.000852

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00440

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152250 Hom.: 3 Cov.: 31 AF XY: 0.00171 AC XY: 127 AN XY: 74416

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00334 Hom.: 4

Bravo AF: 0.00223

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00176 AC: 214

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00350

EpiControl AF: 0.00320

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.077
Sift	Benign	0.59	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.21
MVP		0.21
MPC		0.22
ClinPred		0.012	T
GERP RS		3.9
Varity_R		0.017
gMVP		0.12

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: rs143095808; hg19: chr22-44360335;