6-29672639-G-C

Variant names:

• chr6-29672639-G-C
• rs184974475
• NM_001109809.5:c.1472C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001109809.5(ZFP57):​c.1472C>G​(p.Thr491Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,611,308 control chromosomes in the GnomAD database, including 13 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: ZFP57 NM_001109809.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.434
• Publications: 4 publications found

Genes affected

ZFP57 (HGNC:18791): (ZFP57 zinc finger protein) The protein encoded by this gene is a zinc finger protein containing a KRAB domain. Studies in mouse suggest that this protein may function as a transcriptional repressor. Mutations in this gene have been associated with transient neonatal diabetes mellitus type 1 (TNDM1).[provided by RefSeq, Sep 2009]

MOG (HGNC:7197): (myelin oligodendrocyte glycoprotein) The product of this gene is a membrane protein expressed on the oligodendrocyte cell surface and the outermost surface of myelin sheaths. Due to this localization, it is a primary target antigen involved in immune-mediated demyelination. This protein may be involved in completion and maintenance of the myelin sheath and in cell-cell communication. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MOG Gene-Disease associations (from GenCC):

• narcolepsy 7

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045357347).
• BP6: Variant 6-29672639-G-C is Benign according to our data. Variant chr6-29672639-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 356211.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0022 (335/152254) while in subpopulation AMR AF = 0.00642 (98/15276). AF 95% confidence interval is 0.00539. There are 8 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109809.5. 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
	ZFP57	NM_001109809.5	MANE Select	c.1472C>G	p.Thr491Ser	missense	Exon 5 of 5	NP_001103279.2	Q9NU63-3
	ZFP57	NM_001366333.2		c.1256C>G	p.Thr419Ser	missense	Exon 4 of 4	NP_001353262.1	A0A7I2S1M6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFP57	ENST00000376883.2	TSL:5 MANE Select	c.1472C>G	p.Thr491Ser	missense	Exon 5 of 5	ENSP00000366080.2	Q9NU63-3
	ZFP57	ENST00000488757.6	TSL:1	c.1256C>G	p.Thr419Ser	missense	Exon 4 of 4	ENSP00000418259.2	A0A7I2S1M6
	ZFP57	ENST00000931172.1		c.1472C>G	p.Thr491Ser	missense	Exon 4 of 4	ENSP00000601231.1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152136 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00153 AC: 375 AN: 244546 AF XY: 0.00158

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00258

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00126 AC: 1834 AN: 1459054 Hom.: 5 Cov.: 31 AF XY: 0.00127 AC XY: 924 AN XY: 725444

African (AFR) AF: 0.00203 AC: 68 AN: 33450

American (AMR) AF: 0.00222 AC: 99 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26108

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39652

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86252

European-Finnish (FIN) AF: 0.0000956 AC: 5 AN: 52302

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5762

European-Non Finnish (NFE) AF: 0.00127 AC: 1411 AN: 1110550

Other (OTH) AF: 0.00171 AC: 103 AN: 60288

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152254 Hom.: 8 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74424

African (AFR) AF: 0.00214 AC: 89 AN: 41546

American (AMR) AF: 0.00642 AC: 98 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00185 AC: 126 AN: 68036

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.00230

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00118 AC: 3

ESP6500EA AF: 0.00195 AC: 10

ExAC AF: 0.00171 AC: 199

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Diabetes mellitus, transient neonatal, 1 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Monogenic diabetes (1)
-	-	1	ZFP57-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.2
DANN	Benign	0.46
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.43
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.024
Sift	Benign	0.71	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.40		Gain of disorder (P = 0.0423)
MVP		0.15
MPC		0.38
ClinPred		0.00054	T
GERP RS		2.1
Varity_R		0.030
gMVP		0.038
Mutation Taster		=100/0	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: rs184974475; hg19: chr6-29640416;