rs2224391

Positions:

• chr6-5260703-A-C
• chr6-5260703-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020408.6(LYRM4):​c.31T>G​(p.Ser11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,553,322 control chromosomes in the GnomAD database, including 71,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (16762 hom., cov: 32)
  • Exomes 𝑓: 0.26 (54603 hom.)
• Consequence: LYRM4 NM_020408.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.36

Genes affected

LYRM4 (HGNC:21365): (LYR motif containing 4) The protein encoded by this gene is found in both mitochondria and the nucleus, where it binds cysteine desulfurase and helps free inorganic sulfur for Fe/S clusters. Disruption of this gene negatively impacts mitochondrial and cytosolic iron homeostasis. [provided by RefSeq, Sep 2016]

FARS2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1671281E-5).
• BP6: Variant 6-5260703-A-C is Benign according to our data. Variant chr6-5260703-A-C is described in ClinVar as [Benign]. Clinvar id is 380035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYRM4	NM_020408.6	c.31T>G	p.Ser11Ala	missense_variant	1/3	ENST00000330636.9	NP_065141.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYRM4	ENST00000330636.9	c.31T>G	p.Ser11Ala	missense_variant	1/3	1	NM_020408.6	ENSP00000418787	P1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61612 AN: 151740 Hom.: 16717 Cov.: 32

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.288 AC: 47290 AN: 164260 Hom.: 8411 AF XY: 0.270 AC XY: 23487 AN XY: 87134

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.361

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.265

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.263 AC: 368480 AN: 1401474 Hom.: 54603 Cov.: 42 AF XY: 0.259 AC XY: 178914 AN XY: 692054

Gnomad4 AFR exome AF: 0.802

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.254

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.406 AC: 61707 AN: 151848 Hom.: 16762 Cov.: 32 AF XY: 0.398 AC XY: 29525 AN XY: 74204

Gnomad4 AFR AF: 0.778

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.388

Alfa AF: 0.278 Hom.: 9134

Bravo AF: 0.438

TwinsUK AF: 0.258 AC: 957

ALSPAC AF: 0.248 AC: 956

ESP6500AA AF: 0.738 AC: 3199

ESP6500EA AF: 0.249 AC: 2111

ExAC AF: 0.220 AC: 23291

Asia WGS AF: 0.257 AC: 896 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 20, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Combined oxidative phosphorylation deficiency 19 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.092	T;.;T;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.046	T;T;T;T;T
MetaRNN	Benign	0.000012	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.093
Sift	Benign	0.32	T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;D
Polyphen		0.052	B;.;B;.;.
Vest4		0.061
MPC		0.13
ClinPred		0.035	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.030

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: rs2224391; hg19: chr6-5260936; COSMIC: COSV51166411; COSMIC: COSV51166411;