chr4-144114761-G-A

Position:

• chr4-144114761-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_002099.8(GYPA):​c.364C>T​(p.Pro122Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GYPA NM_002099.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.372

Genes affected

GYPA (HGNC:4702): (glycophorin A (MNS blood group)) Glycophorins A (GYPA) and B (GYPB) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups. In addition to the M or N and S or s antigens that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include all the variants of the Miltenberger complex and several isoforms of Sta, as well as Dantu, Sat, He, Mg, and deletion variants Ena, S-s-U- and Mk. Most of the variants are the result of gene recombinations between GYPA and GYPB. [provided by RefSeq, Jul 2008]

LOC105377460 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07242361).
• BP6: Variant 4-144114761-G-A is Benign according to our data. Variant chr4-144114761-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2488847.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYPA	NM_002099.8	c.364C>T	p.Pro122Ser	missense_variant	6/7	ENST00000641688.3	NP_002090.4
LOC105377460	XR_002959803.2	n.4802G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYPA	ENST00000641688.3	c.364C>T	p.Pro122Ser	missense_variant	6/7		NM_002099.8	ENSP00000493142	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420122 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 709252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Feb 23, 2023

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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0030
DANN	Benign	0.82
DEOGEN2	Benign	0.0075	.;T;T;.;.;.;.;.;T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.61	T;.;T;T;.;.;T;T;T;T;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.080	.;.;N;N;.;.;.;.;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.30	.;.;T;T;.;.;.;.;T;T;T;T
Sift4G	Benign	0.98	T;.;T;T;.;T;.;.;T;T;T;T
Polyphen		0.011, 0.0010, 0.0040	.;.;.;.;.;.;.;.;B;B;B;.
Vest4		0.074
MutPred		0.56		.;Gain of phosphorylation at P122 (P = 0.0209);Gain of phosphorylation at P122 (P = 0.0209);.;.;.;.;.;.;.;.;.;
MVP		0.030
MPC		0.059
ClinPred		0.092	T
GERP RS		-7.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.010

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1730682576; hg19: chr4-145035914;