NM_015380.5:c.136G>A

Variant names:

• chr22-43964455-G-A
• rs143095808
• NM_015380.5:c.136G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015380.5(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. 14/22 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 NM_015380.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.64
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 714564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015380.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMM50	NM_015380.5	MANE Select	c.136G>A	p.Val46Ile	missense	Exon 3 of 15	NP_056195.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMM50	ENST00000350028.5	TSL:1 MANE Select	c.136G>A	p.Val46Ile	missense	Exon 3 of 15	ENSP00000345445.4	Q9Y512
	SAMM50	ENST00000943220.1		c.136G>A	p.Val46Ile	missense	Exon 3 of 15	ENSP00000613279.1
	SAMM50	ENST00000854677.1		c.136G>A	p.Val46Ile	missense	Exon 3 of 15	ENSP00000524736.1

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

GnomAD2 exomes AF: 0.00180 AC: 452 AN: 250866 AF XY: 0.00171

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 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

African (AFR) AF: 0.000606 AC: 20 AN: 32978

American (AMR) AF: 0.000852 AC: 38 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85668

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53372

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00440 AC: 4785 AN: 1088152

Other (OTH) AF: 0.00283 AC: 168 AN: 59462

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

African (AFR) AF: 0.000843 AC: 35 AN: 41536

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00398 AC: 271 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00323 Hom.: 5

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.6
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
Mutation Taster		=277/23	polymorphism

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

Other links and lift over

dbSNP: rs143095808; hg19: chr22-44360335;